Tricyclic crbn ligands and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of CRBN, and the treatment of CRBN-mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.16/502,529, filed Jul. 3, 2019, which claims the benefit under 35 U.S.C.§ 119(e) of U.S. Provisional Application No. 62/694,924, filed Jul. 6,2018, U.S. Provisional Application No. 62/820,634, filed Mar. 19, 2019,and U.S. Provisional Application No. 62/863,949, filed Jun. 20, 2019,the content of each of which is incorporated herein in its entirety byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forbinding and modulating the activity of cereblon (CRBN). The inventionalso provides pharmaceutically acceptable compositions comprisingcompounds of the present invention and methods of using saidcompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The Ubiquitin-Proteasome Pathway (UPP) is a critical pathway thatregulates key regulator proteins and degrades misfolded or abnormalproteins. UPP is central to multiple cellular processes, and ifdefective or imbalanced, it leads to pathogenesis of a variety ofdiseases. The covalent attachment of ubiquitin to specific proteinsubstrates is achieved through the action of E3 ubiquitin ligases. Theseligases comprise over 500 different proteins and are categorized intomultiple classes defined by the structural element of their E3functional activity.

UPP plays a key role in the degradation of short-lived and regulatoryproteins important in a variety of basic cellular processes, includingregulation of the cell cycle, modulation of cell surface receptors andion channels, and antigen presentation. The pathway has been implicatedin several forms of malignancy, in the pathogenesis of several geneticdiseases (including cystic fibrosis, Angelman's syndrome, and Liddlesyndrome), in immune surveillance/viral pathogenesis, and in thepathology of muscle wasting. Many diseases are associated with anabnormal UPP and negatively affect cell cycle and division, the cellularresponse to stress and to extracellular modulators, morphogenesis ofneuronal networks, modulation of cell surface receptors, ion channels,the secretory pathway, DNA repair and biogenesis of organelles.

Aberrations in the process have recently been implicated in thepathogenesis of several diseases, both inherited and acquired. Thesediseases fall into two major groups: (a) those that result from loss offunction with the resultant stabilization of certain proteins, and (b)those that result from gain of function, i.e. abnormal or accelerateddegradation of the protein target.

Cereblon (CRBN) interacts with damaged DNA binding protein 1 and formsan E3 ubiquitin ligase complex with Cullin 4 where it functions as asubstrate receptor in which the proteins recognized by CRBN might beubiquitinated and degraded by proteasomes.

A new role for CRBN has been identified; i.e., the binding ofimmunomodulatory drugs (IMiDs), e.g. thalidomide, to CRBN has now beenassociated with teratogenicity and also the cytotoxicity of IMiDs,including lenalidomide, which are widely used to treat multiple myelomapatients. CRBN is likely a key player in the binding, ubiquitination anddegradation of factors involved in maintaining function of myelomacells. These new findings regarding the role of CRBN in IMiD actionstimulated intense investigation of CRBN's downstream factors involvedin maintaining regular function of a cell (Chang and Stewart Int JBiochem Mol Biol. 2011; 2(3): 287-294).

Accordingly, there remains a need to find CRBN ligands useful astherapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective as CRBNligands. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with CRBN. Such diseases, disorders,or conditions include those described herein.

Compounds provided by this invention are also useful for the study ofCRBN and associated proteins in biological and pathological phenomena;the study of CRBN occurring in bodily tissues; and the comparativeevaluation of new CRBN ligands or other regulators of CRBN in vitro orin vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas CRBN ligands. As defined herein, the terms “binder,” “modulator,” and“ligand” are used interchangeably and describe a compound that binds to,modulates or is a ligand for CRBN.

In certain embodiments, the present invention provides a compound offormula I-a:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring D, it is intended, and one of ordinary skill in theart would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring D including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula I-a′:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein each of Ring B, Ring C, and Ring D is independently a fused ringselected from 6-membered aryl, 6-membered heteroaryl containing 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5to 7-membered saturated or partially unsaturated carbocyclyl, 5 to7-membered saturated or partially unsaturated heterocyclyl ring with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;

-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring B, Ring C, and Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B or Ring C arefused to Ring D.

In certain embodiments, the present invention provides a compound offormula I-b:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or.    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic ring system selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring E is a fused ring selected from a 7-9 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring E is optionally further substituted    with 1-2 oxo groups;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring B and RingE, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B and Ring E are fused.

Where a point of attachment of

is depicted on Ring B and Ring E, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B and Ring E arefused.

In certain embodiments, the present invention provides a compound offormula I-c:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;

Ring A is a tricyclic ring system selected from

wherein

-   each of Ring F and G is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring F, Ring G,and Ring H, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring F, Ring G, and Ring H are fused.

Where a point of attachment of

is depicted on Ring F, Ring G, and Ring H, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring F, Ring G, andRing H are fused.

In certain embodiments, the present invention provides a compound offormula I-d:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring D, and Ring C is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —CR₂—, —CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or    —CR═CR—;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring D,or Ring C, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring B, Ring D, or Ring C includingthe carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring B, Ring D, or Ring C, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring B, Ring D, orRing C, including the carbon atom to which Ring B or Ring C are fused toRing D.

In certain embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring D, it is intended, and one of ordinary skill in theart would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring D including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula II′:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring B, Ring C, and Ring D, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring A including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula II-a:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B and Ring C is independently a fused ring selected    from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered    saturated or partially unsaturated carbocyclyl, 5 to 7-membered    saturated or partially unsaturated heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen or    sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently    selected from nitrogen, oxygen or sulfur;-   Ring D is a fused ring selected from aryl containing 0-3 nitrogens,    saturated or partially unsaturated carbocyclyl, saturated or    partially unsaturated heterocyclyl ring with 1-2 heteroatoms    independently selected from nitrogen, oxygen, silicon, or sulfur, or    heteroaryl with 1-3 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   is a single or double bond; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring C,and Ring D, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring D, it is intended, and one of ordinary skill in theart would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring D including thecarbon atom to which Ring B or Ring C are fused to Ring D.

In certain embodiments, the present invention provides a compound offormula II-b:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B and Ring C is independently a fused ring selected    from 6-membered aryl containing 0-2 nitrogens, 5 to 7-membered    saturated or partially unsaturated carbocyclyl, 5 to 7-membered    saturated or partially unsaturated heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   is a single or double bond; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

Where a point of attachment of —(R²)_(m) is depicted on Ring B or RingC, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom ring to which Ring B or Ring C is fused.

In certain embodiments, the present invention provides a compound offormula II-c:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic ring system selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring E is a fused ring selected from a 7-9 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring E is optionally further substituted    with 1-2 oxo groups;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring B and RingE, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring B and Ring E are fused.

Where a point of attachment of

is depicted on Ring B and Ring E, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring B and Ring E arefused.

In certain embodiments, the present invention provides a compound offormula II-d:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring system selected from

wherein

-   each of Ring F and G is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of —(R²)_(m) is depicted on Ring F, Ring G,and Ring H, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on Ring Aand may also be at any available carbon or nitrogen atom on Ring Aincluding the carbon atom to which Ring F, Ring G, and Ring H are fused.

Where a point of attachment of

is depicted on Ring F, Ring G, and Ring H, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on Ring A and may also be at any available carbon or nitrogenatom on Ring A including the carbon atom to which Ring F, Ring G, andRing H are fused.

In certain embodiments, the present invention provides a compound offormula III or IV:

or a pharmaceutically acceptable salt thereof, wherein:

-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring D, and Ring C is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —CR₂—, —CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or    —CR═CR—;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;    and-   R⁴, R¹⁰, R¹¹, R¹⁵, W¹, W², and X is as defined in WO 2019/099868,    the entirety of each of which is herein incorporated by reference.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, Ring D,or Ring C, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring B, Ring D, or Ring C includingthe carbon atom to which Ring B or Ring C are fused to Ring D.

Where a point of attachment of

is depicted on Ring B, Ring D, or Ring C, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring B, Ring D, orRing C, including the carbon atom to which Ring B or Ring C are fused toRing D.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈(or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 9-membered monocyclic or 7- to 11-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms“heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘); —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘)₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; —SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a provided compound may be substituted with one or moredeuterium atoms.

As used herein, the term “provided compound” refers to any genus,subgenus, and/or species set forth herein.

As used herein, the term “binder” or “ligand” is defined as a compoundthat binds to CRBN with measurable affinity. In certain embodiments, acompound has a binding constant of less than about 50 μM, less thanabout 1 μM, less than about 500 nM, less than about 100 nM, less thanabout 10 nM, or less than about 1 nM.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably modulate,” as usedherein, means a measurable change in a CRBN activity between a samplecomprising a compound of the present invention, or composition thereof,and CRBN, and an equivalent sample comprising CRBN, in the absence ofsaid compound, or composition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-2 heteroatoms independently selected from nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-a′:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula I-a′ above is provided as acompound of formula I-a″ or formula I-a′″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring A, L, X¹, X², X³, R¹, R², and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-b:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic ring system selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring E is a fused ring selected from a 7-9 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring E is optionally further substituted    with 1-2 oxo groups;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula I-b above is provided as acompound of formula I-b′ or formula I-b″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring A, L, X¹, X², X³, R¹, R², and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-c:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring system selected from

wherein

-   each of Ring F and G is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula I-c above is provided as acompound of formula I-c′ or formula I-c″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring A, L, X¹, X², X³, R¹, R², and m is as defined above.

In certain embodiments, the present invention provides a compound offormula I-d:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring D, and Ring C is independently a use ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —CR₂—, —CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or    —CR═CR—;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula I-d above is provided as acompound of formula I-d′ or formula I-d″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring B, Ring C, Ring D, L, L¹, R¹, R², X¹, X², X³, and m is    as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-2 heteroatoms independently selected from nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

As described above, in certain embodiments, the present inventionprovides a compound of formula II′:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring C, and Ring D is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula II′ above is provided as acompound of formula II″ or formula II′″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring A, L, X¹, R¹, R², and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula II-a:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or: two R groups on the    same nitrogen are taken together with their intervening atoms to    form a 4-7 membered saturated, partially unsaturated, or heteroaryl    ring having 0-3 heteroatoms, in addition to the nitrogen,    independently selected from nitrogen, oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B and Ring C is independently a fused ring selected    from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered    saturated or partially unsaturated carbocyclyl, 5 to 7-membered    saturated or partially unsaturated heterocyclyl ring with 1-2    heteroatoms independently selected from nitrogen, oxygen or sulfur,    or 5-membered heteroaryl with 1-3 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring D is a fused ring selected from aryl containing 0-3 nitrogens,    saturated or partially unsaturated carbocyclyl, saturated or    partially unsaturated heterocyclyl ring with 1-2 heteroatoms    independently selected from nitrogen, oxygen or sulfur, or    heteroaryl with 1-3 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   is a single or double bond; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

As described above, in certain embodiments, the present inventionprovides a compound of formula II-b:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,    —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,    —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or    —N(R)S(O)₂R;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B and Ring C is independently a fused ring selected    from 6-membered aryl containing 0-2 nitrogens, 5 to 7-membered    saturated or partially unsaturated carbocyclyl, 5 to 7-membered    saturated or partially unsaturated heterocyclyl ring with 1-2    heteroatoms independently selected from nitrogen, oxygen or sulfur,    or 5-membered heteroaryl with 1-3 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   is a single or double bond; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

As defined above and described herein, in certain embodiments, thepresent invention provides a compound of formula II-c:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or.    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic ring system selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring E is a fused ring selected from a 7-9 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring E is optionally further substituted    with 1-2 oxo groups;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula II-c above is provided as acompound of formula II-c′ or formula II-c″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring A, L, X¹, R¹, R², and m is as defined above.

In some embodiments, a compound of formula II-c above is provided as acompound of formula II-c-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring B, X¹, R¹, R², and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula II-d:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring system selected from

wherein

-   each of Ring F and G is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, a compound of formula II-d above is provided as acompound of formula II-d′ or formula II-d″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring A, L, X¹, R¹, R², and m is as defined above.

In some embodiments, a compound of formula II-d above is provided as acompound of formula II-d-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Ring F, Ring G, X¹, R¹, R², and m is as defined above.

In certain embodiments, the present invention provides a compound offormula III or IV:

or a pharmaceutically acceptable salt thereof, wherein:

-   each R² is independently hydrogen, deuterium, —R³, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each L is independently a covalent bond or a bivalent, saturated or    unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by —C(D)(H)—,    —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,    —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,    —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —OC(O)N(R)—, —N(R)C(O)O—,

wherein:

-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-7    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R³ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A is a tricyclic ring selected from

wherein

-   each of Ring B, Ring D, and Ring C is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —CR₂—, —CFR—, —CF₂—, —NR—, —S—, —S(O)₂— or    —CR═CR—;-   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;    and-   R⁴, R¹⁰, R¹¹, R¹⁵, W¹, W², and X is as defined in WO 2019/099868,    the entirety of each of which is herein incorporated by reference.

As defined above and described herein, X¹ is a bivalent moiety selectedfrom a cova covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—,—P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, or

lent bond, —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CH₂—. In some embodiments, X¹ is —CHCF₃—. In some embodiments, X¹ is—SO₂—. In some embodiments, X¹ is —S(O)—. In some embodiments, X¹ is—P(O)R—. In some embodiments, X¹ is —P(O)OR—. In some embodiments, X¹ is—P(O)NR₂—. In some embodiments, X¹ is —C(O)—. In some embodiments, X¹ is—C(S)—. In some embodiments, X¹ is

In some embodiments, X¹ is selected from those depicted in Table 1,below.

As defined above and described herein, X² is a carbon atom or siliconatom.

In some embodiments, X² is a carbon atom. In some embodiments, X² is asilicon atom.

In some embodiments, X² is selected from those depicted in Table 1,below.

As defined above and described herein, X³ is a bivalent moiety selectedfrom —CH₂—, —NR—, —O—, —S—, or —Si(R₂)—.

In some embodiments, X³ is —CH₂—. In some embodiments, X³ is —NR—. Insome embodiments, X³ is —O—. In some embodiments, X³ is —S—. In someembodiments, X² is —Si(R₂)—.

In some embodiments, X³ is selected from those depicted in Table 1,below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR,—P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or an optionallysubstituted C₁₋₄ aliphatic.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is halogen. In some embodiments, R¹is —CN. In some embodiments, R¹ is —OR. In some embodiments, R¹ is —SR.In some embodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R.In some embodiments, R¹ is —NR₂. In some embodiments, R¹ is —P(O)(OR)₂.In some embodiments, R¹ is —P(O)(NR₂)OR. In some embodiments, R¹ is—P(O)(NR₂)₂. In some embodiments, R¹ is —Si(OH)₂R. In some embodiments,R¹ is —Si(OH)(R)₂. In some embodiments, R¹ is —Si(R₃). In someembodiments, R¹ is an optionally substituted C₁₋₄ aliphatic.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogen,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: two Rgroups on the same nitrogen are taken together with their interveningatoms to form a 4-7 membered saturated, partially unsaturated, orheteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R is optionallysubstituted phenyl. In some embodiments, R is optionally substituted 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R is optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, two R groups on the samenitrogen are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined above and described herein, each R² is independentlyhydrogen, deuterium, —R³, halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R₃),—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR,—C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R.

In some embodiments, R² is hydrogen. In some embodiments, R² isdeuterium. In some embodiments, R² is —R³. In some embodiments, R² ishalogen. In some embodiments, R² is —CN. In some embodiments, R² is—NO₂. In some embodiments, R² is —OR. In some embodiments, R² is —SR. Insome embodiments, R² is —NR₂. In some embodiments, R² is —P(O)(OR)₂. Insome embodiments, R² is —P(O)(NR₂)OR. In some embodiments, R² is—P(O)(NR₂)₂. In some embodiments, R² is —Si(OH)₂R. In some embodiments,R² is —Si(OH)(R)₂. In some embodiments, R² is —Si(R₃). In someembodiments, R² is —S(O)₂R. In some embodiments, R² is —S(O)₂NR₂. Insome embodiments, R² is —S(O)R. In some embodiments, R² is —C(O)R. Insome embodiments, R² is —C(O)OR. In some embodiments, R² is —C(O)NR₂. Insome embodiments, R² is —C(O)N(R)OR. In some embodiments, R² is—C(R)₂N(R)C(O)R. In some embodiments, R² is —C(R)₂N(R)C(O)N(R)₂. In someembodiments, R² is —OC(O)R. In some embodiments, R² is —OC(O)NR₂. Insome embodiments, R² is —N(R)C(O)OR. In some embodiments, R² is—N(R)C(O)R. In some embodiments, R² is —N(R)C(O)NR₂. In someembodiments, R² is —N(R)S(O)₂R.

In some embodiments, R² is —OH. In some embodiments, R² is —NH₂. In someembodiments, R² is —CH₂NH₂. In some embodiments, R² is —CH₂NHCOMe. Insome embodiments, R² is —CH₂NHCONHMe. In some embodiments, R² is—NHCOMe. In some embodiments, R² is —NHCONHEt. In some embodiments, R²is —SiMe₃. In some embodiments, R² is Br. In some embodiments, R² is—SiMe(OH)₂. In some embodiments, R² is

In some embodiments, R² is Br. In some embodiments, R² is Cl. In someembodiments, R₂ is F. In some embodiments, R₂ is Me. In someembodiments, R₂ is —NHMe. In some embodiments, R² is —NMe₂. In someembodiments, R² is —NHCO₂Et. In some embodiments, R² is —CN. In someembodiments, R² is —CH₂Ph. In some embodiments, R² is —NHCO₂tBu. In someembodiments, R² is —CO₂tBu. In some embodiments, R² is —OMe. In someembodiments, R² is —CF₃.

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined above and described herein, L is independently a covalentbond or a bivalent, saturated or unsaturated, straight or branched C₁₋₅₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by —C(D)(H)—, —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—,—Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—,—OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—,—N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—,

wherein each -Cy- is independently an optionally substituted bivalentring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-7membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-7 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclicheteroarylenyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, L is independently a covalent bond. In someembodiments, L is independently a bivalent, saturated or unsaturated,straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methyleneunits of L are independently replaced by —C(D)(H)—, —C(D)₂-, -Cy-, —O—,—N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—,—P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,—N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—,—N(R)C(O)O—,

In some embodiments, each -Cy- is independently an optionallysubstituted bivalent phenylenyl. In some embodiments, each -Cy- isindependently an optionally substituted 8-10 membered bicyclic arylenyl.In some embodiments, each -Cy- is independently an optionallysubstituted 4-7 membered saturated or partially unsaturatedcarbocyclylenyl. In some embodiments, each -Cy- is independently anoptionally substituted 4-7 membered saturated or partially unsaturatedspiro carbocyclylenyl. In some embodiments, each -Cy- is independentlyan optionally substituted 8-10 membered bicyclic saturated or partiallyunsaturated carbocyclylenyl. In some embodiments, each -Cy- isindependently an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, each -Cy- is independently an optionally substituted 4-7membered saturated or partially unsaturated spiro heterocyclylenylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each -Cy- is independently an optionallysubstituted 8-10 membered bicyclic saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, each -Cy- isindependently an optionally substituted 5-6 membered heteroarylenylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each -Cy- is independently an optionallysubstituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is

In some embodiments, -Cy- is selected from those depicted in Table 1,below.

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments L is

In some embodiments, L is

In some embodiments, L is

In some embodiments L is

In some embodiments, L is

In some embodiments, L is

In

some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is selected from those depicted in Table 1,below.

As defined above and described herein, each R³ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R³ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R³ is an optionally substituted phenyl. In someembodiments, R³ is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R³ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, each of Ring B, Ring C, and RingD is independently a fused ring selected from 6-membered aryl,6-membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, each Ring B, Ring C, and Ring D is independently a6-membered aryl. In some embodiments, each Ring B, Ring C, and Ring D isindependently a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each Ring B, Ring C, and Ring D is independently a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each Ring B, Ring C, and Ring D is independently a 5 to7-membered saturated or partially unsaturated heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, each Ring B, Ring C, and Ring Dis independently a 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring B, Ring C, and Ring D is independentlyselected from those depicted in Table 1, below.

As defined above and described herein, Ring E is a ring selected from a7-9 membered saturated or partially unsaturated carbocyclyl orheterocyclyl ring with 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E isoptionally further substituted with 1-2 oxo groups.

In some embodiments, Ring E is a ring selected from a 7-9 memberedsaturated or partially unsaturated carbocyclyl or heterocyclyl ring with1-3 heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, wherein Ring E is optionally further substitutedwith 1-2 oxo groups.

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is

In some embodiments, Ring E is selected from those depicted in Table 1,below.

As defined above and described herein, each of Ring F and Ring G isindependently a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur

In some embodiments, each of Ring F and Ring G is independently a6-membered aryl. In some embodiments, each of Ring F and Ring G isindependently a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each of Ring F and Ring G is independently a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each of Ring F and Ring G is independently a 5 to7-membered saturated or partially unsaturated heterocyclyl ring with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, each of Ring F and Ring G isindependently a 5-membered heteroaryl with 1-3 heteroatoms independentlyselected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring F and Ring G is independently

In some embodiments, each Ring F and Ring G is independently

In some embodiments, each Ring F and Ring G is independently

In some embodiments, each Ring F and Ring G is independently

In some embodiments, Ring F and Ring G is independently

In some embodiments, Ring F and Ring G is independently is

In some embodiments, Ring F and Ring G is independently

In some embodiments, Ring F and Ring G is independently

In some embodiments, each of Ring F and G is independently selected fromthose depicted in Table 1, below.

As defined above and described herein, Ring H is a fused ring selectedfrom a 7-12 membered saturated or partially unsaturated carbocyclyl orheterocyclyl with 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionallyfurther substituted with 1-2 oxo groups.

In some embodiments, Ring H is a 7-12 membered saturated or partiallyunsaturated carbocyclyl. In some embodiments, Ring H is a 7-12 memberedsaturated or partially unsaturated heterocyclyl with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur.In some embodiments, Ring H is optionally further substituted with 1-2oxo groups.

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiment, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, Ring D is a fused ring selectedfrom aryl containing 0-3 nitrogens, saturated or partially unsaturatedcarbocyclyl, saturated or partially unsaturated heterocyclyl ring with1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur,or heteroaryl with 1-3 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, Ring D is an aryl containing 0-2 nitrogen atoms. Insome embodiments, Ring D is a saturated or partially unsaturatedcarbocyclyl. In some embodiments, each Ring D is a saturated orpartially unsaturated heterocyclyl with 1-3 heteroatoms independentlyselected from nitrogen, oxygen, silicon, or sulfur. In some embodiments,Ring D is a heteroaryl with 1-3 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is selected from those depicted in Table 1,below.

As defined above and described herein,

is a single or double bond.

In some embodiments,

is a single bond. In some embodiments,

is a double bond.

In some embodiments,

is selected from those depicted in Table 1, below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8. In some embodiments, mis 9. In some embodiments, m is 10. In some embodiments, m is 11. Insome embodiments, m is 12. In some embodiments, m is 13. In someembodiments, m is 14. In some embodiments, m is 15. In some embodiments,m is 16.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiment, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, each Ring B and Ring C isindependently a fused ring selected from 6-membered aryl containing 0-2nitrogen atoms, 5 to 7-membered saturated or partially unsaturatedcarbocyclyl, 5 to 7-membered saturated or partially unsaturatedheterocyclyl with 1-2 heteroatoms independently selected from nitrogen,oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring B and Ring C is independently a6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, eachRing B and Ring C is independently a 5 to 7-membered saturated orpartially unsaturated carbocyclyl. In some embodiments, each Ring B andRing C is independently a 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-2 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur. In some embodiments, each Ring B andRing C is independently a 5-membered heteroaryl with 1-3 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently is

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently selected fromthose depicted in Table 1, below.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein,

is a single or double bond

In some embodiments,

is a single bond. In some embodiments, is a double bond.

In some embodiments,

is selected from those depicted in Table 1, below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, or8.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8.

In some embodiments, m is selected from those depicted in Table 1,below.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds I-# Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably bind CRBN, or a mutant thereof, ina biological sample or in a patient. In certain embodiments, the amountof compound in compositions of this invention is such that is effectiveto measurably bind CRBN, or a mutant thereof, in a biological sample orin a patient. In certain embodiments, a composition of this invention isformulated for administration to a patient in need of such composition.In some embodiments, a composition of this invention is formulated fororal administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an active metabolite or residue thereof.

As used herein, the term “active metabolite or residue thereof” meansthat a metabolite or residue thereof is also a binder of CRBN, or amutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for themodulation of CRBN. In some embodiments the protein complex bound by thecompounds and methods of the invention comprises CRBN.

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance. Cereblon forms an E3 ubiquitin ligasecomplex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A),and regulator of cullins 1 (ROC1). This complex ubiquitinates a numberof other proteins. Through a mechanism which has not been completelyelucidated, cereblon ubquitination of target proteins results inincreased levels of fibroblast growth factor 8 (FGF8) and fibroblastgrowth factor 10 (FGF10). FGF8 in turn regulates a number ofdevelopmental processes, such as limb and auditory vesicle formation.The net result is that this ubiquitin ligase complex is important forlimb outgrowth in embryos. In the absence of cereblon, DDB1 forms acomplex with DDB2 that functions as a DNA damage-binding protein.

Accordingly, compounds that bind CRBN are beneficial, especially thosewith selectivity over other E3 ligases. Such compounds should deliver apharmacological response that favorably treats one or more of theconditions described herein without the side-effects associated with thebinding of other E3 ligases.

Even though CRBN ligands are known in the art, there is a continuingneed to provide novel ligands having more effective or advantageouspharmaceutically relevant properties. For example, compounds withincreased activity, selectivity over other E3 ligases, and ADMET(absorption, distribution, metabolism, excretion, and/or toxicity)properties. Thus, in some embodiments, the present invention providesbinders of CRBN which show selectivity over other E3 ligases.

The activity of a compound utilized in this invention as an binder ofCRBN, or a mutant thereof, may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine the subsequentfunctional consequences, or activity of activated CRBN, or a mutantthereof. Alternate in vitro assays quantitate the ability of thecompound to bind to CRBN. Compound binding may be measured byradiolabeling the compound prior to binding, isolating the compound/CRBNcomplex and determining the amount of radiolabel bound. Alternatively,compound binding may be determined by running a competition experimentwhere new compounds are incubated with CRBN bound to known radioligands.Representative in vitro and in vivo assays useful in assaying a CRBNbinder include those described and disclosed in, Boichenko et al. J.Med. Chem. (2016) 59, 770-774 and Iconomou and Saunders BiochemicalJournal (2016) 473, 4083-4101, each of which is herein incorporated byreference in its entirety. Detailed conditions for assaying a compoundutilized in this invention as a binder of CRBN, or a mutant thereof, areset forth in the Examples below.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are binders of CRBN and are therefore useful fortreating one or more disorders associated with activity of CRBN ormutants thereof. Thus, in certain embodiments, the present inventionprovides a method for treating a CRBN-mediated disorder comprising thestep of administering to a patient in need thereof a compound of thepresent invention, or pharmaceutically acceptable composition thereof.

As used herein, the term “CRBN-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which CRBN or a mutant thereof is known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in whichCRBN, or a mutant thereof, is known to play a role. Such CRBN-mediateddisorders include but are not limited to proliferative disorders,neurological disorders and disorders associated with transplantation.

In some embodiments, the present invention provides a method fortreating one or more disorders, wherein the disorders are selected fromproliferative disorders, neurological disorders and disorders associatedwith transplantation, said method comprising administering to a patientin need thereof, a pharmaceutical composition comprising an effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the disorder is a proliferative disorder. In someembodiments, the proliferative disorder is a hematological cancer. Insome embodiments, the proliferative disorder is a leukemia. In someembodiments, the proliferative disorder is a leukemia selected from thegroup consisting of anemia, acute leukemia, acute lymphoblastic leukemia(ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia,acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), adultacute basophilic leukemia, adult acute eosinophilic leukemia, adultacute megakaryoblastic leukemia, adult acute minimally differentiatedmyeloid leukemia, adult acute monoblastic leukemia, adult acutemonocytic leukemia, adult acute myeloblastic leukemia with maturation,adult acute myeloblastic leukemia without maturation, adult acutemyeloid leukemia with abnormalities, adult acute myelomonocyticleukemia, adult erythroleukemia, adult pure erythroid leukemia,secondary acute myeloid leukemia, untreated adult acute myeloidleukemia, adult acute myeloid leukemia in remission, adult acutepromyelocytic leukemia with PML-RARA, alkylating agent-related acutemyeloid leukemia, prolymphocytic leukemia, and chronic myelomonocyticleukemia.

In some embodiments, the proliferative disorder is a lymphoma. In someembodiments, the proliferative disorder is a lymphoma selected from thegroup consisting of adult grade III lymphomatoid granulomatosis, adultnasal type extranodal NK/T-cell lymphoma, anaplastic large celllymphoma, angioimmunoblastic T-cell lymphoma, cutaneous B-Cellnon-Hodgkin lymphoma, extranodal marginal zone lymphoma ofmucosa-associated lymphoid tissue, hepatosplenic T-cell lymphoma,intraocular lymphoma, lymphomatous involvement of non-cutaneousextranodal site, mature T-cell and NK-cell non-Hodgkin lymphoma, nodalmarginal zone lymphoma, post-transplant lymphoproliferative disorder,recurrent adult Burkitt lymphoma, recurrent adult diffuse large celllymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adultdiffuse small cleaved cell lymphoma, recurrent adult grade IIIlymphomatoid granulomatosis, recurrent adult immunoblastic lymphoma,recurrent adult lymphoblastic lymphoma, recurrent adult T-cellleukemia/lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma,recurrent grade 1 follicular lymphoma, recurrent grade 2 follicularlymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle celllymphoma, recurrent marginal zone lymphoma, recurrent mycosis fungoidesand Sezary syndrome, recurrent small lymphocytic lymphoma, refractorychronic lymphocytic leukemia, refractory hairy cell leukemia, Richtersyndrome, small intestinal lymphoma, splenic marginal zone lymphoma,T-cell large granular lymphocyte leukemia, testicular lymphoma,Waldenstrom macroglobulinemia, adult T-cell leukemia-lymphoma,peripheral T-cell lymphoma, B-cell lymphoma, Hodgkin's disease,cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma,mantle cell lymphoma, non-Hodgkins lymphoma, central nervous systemlymphoma, refractory primary-cutaneous large B-cell lymphoma (Leg-type),relapsed or refractory chronic lymphocytic leukemia, refractory anemia,refractory anemia with excess blasts, refractory anemia with ringedsideroblasts, refractory cytopenia with multilineage dysplasia, andsecondary myelodysplastic syndromes.

In some embodiments, the disorder is a neurological disorder. In someembodiments, the neurological disorder is Alzheimer's disease.

In some embodiments, the disorder is associated with transplantation. Insome embodiments the disorder associated with transplantation istransplant rejection, or graft versus host disease.

In some embodiments, the proliferative disorder is a cancer or tumor. Insome embodiments, the proliferative disorder is a cancer or tumorselected from the group consisting of head and neck cancer, livercancer, hormone-refractory prostate cancer, kidney cancer, smallintestine cancer, glioblastoma, non-small cell lung cancer, ovariancancer, endometrial cancer, esophageal cancer, colon cancer, lungcancer, brain and central nervous system tumors, gastrointestinalcarcinoid tumor, islet cell tumor, and childhood solid tumor.

In some embodiments, the proliferative disorder is a myeloma. In someembodiments, the proliferative disorder is a multiple myeloma.

In some embodiments, the proliferative disorder is a myeloma selectedfrom the group consisting of refractory multiple myeloma, stage Imultiple myeloma, stage II multiple myeloma, stage III multiple myeloma,smoldering plasma cell myeloma, and plasma cell myeloma.

In some embodiments, the proliferative disorder is selected from thegroup consisting of hepatocellular carcinoma, melanoma, malignantmelanoma, thyroid neoplasms, urinary bladder neoplasms, amyotrophiclateral sclerosis (ALS), sickle cell anemia, ankylosing spondylitis,arachnoiditis, arterivenous malformation, and hereditary hemorrhagictelangiectasia.

In some embodiments, the disorder is selected from the group consistingof AIDS-related Kaposi sarcoma, amyloidosis, hematochezia, melena,autism, burning mouth syndrome associated with HIV infection,hepatocellular carcinoma, non-small-cell lung carcinoma, central nervoussystem neoplasms, medulloblastoma, chronic myeloproliferative disorders,secondary myelofibrosis, chronic pancreatitis, chronic prostatitis,complex regional pain syndrome (RSD), Type 1 complex regional painsyndrome, Crohn's disease, cutaneous lupus erythematosus (CLE), discoidlupus erythematosus, endometriosis, neoplastic syndrome,gastrointestinal hemorrhage, gastrointestinal vascular malformation,hepatitis C, high grade squamous intra-epithelial lesion (HSIL), HIVwasting syndrome, HIV-associated mycobacterium infections,HIV-associated tuberculosis, HIV-associated aphthous stomatitis,HIV-associated avium-intracellulare infection, idiopathic pulmonaryfibrosis (IPF), Langerhans cell histiocytosis (LCH), histiocytosis,Erdheim-Chester disease, histiocytic light chain deposition disease,myelofibrosis, myeloproliferative neoplasms, neurofibromatosis type 1,recurrent central nervous system neoplasm, recurrent childhood brainstem glioma, recurrent childhood visual pathway glioma, refractorycentral nervous system neoplasm, nonmalignant monoclonal gammopathy ofundetermined significance (MGUS), primary amyloidosis, primarymyelofibrosis, primary sclerosing cholangitis, plaque-type psoriasis,pulmonary fibrosis, radiation injuries, radiculopathy, recurrent uterinecorpus sarcoma, uterine carcinosarcoma, refractory epilepsy,sarcoidosis, systemic scleroderma, systemic sclerosis, Sjogren'sSyndrome, xerostomia, soft tissue sarcoma, thalassemia, and uveitis.

In some embodiments, compounds of the present invention bind to CRBN,altering the specificity of the complex to induce the ubiquitination anddegradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factorsessential for multiple myeloma growth.

In some embodiments, compounds of the present invention bind to CRBN,altering the specificity of the complex to induce the ubiquitination anddegradation of a complex-associated protein selected from the groupconsisting of A1BG, A1CF, A2M, A2ML1, A3GALT2, A4GALT, A4GNT, AAAS,AACS, AADAC, AADACL2, AADACL3, AADACL4, AADAT, AAED1, AAGAB, AAK1,AAMDC, AAMP, AANAT, AAR2, AARD, AARS, AARS2, AARSD1, AASDH, AASDHPPT,AASS, AATF, AATK, AATK-AS1, ABAT, ABCA1, ABCA10, ABCA12, ABCA13, ABCA2,ABCA3, ABCA4, ABCA5, ABCA6, ABCA7, ABCA8, ABCA9, ABCB1, ABCB10, ABCB11,ABCB4, ABCB5, ABCB6, ABCB7, ABCB8, ABCB9, ABCC1, ABCC10, ABCC11, ABCC12,ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC8, ABCC9, ABCD1, ABCD2, ABCD3,ABCD4, ABCEl, ABCF1, ABCF2, ABCF3, ABCG1, ABCG2, ABCG4, ABCG5, ABCG8,ABHD1, ABHD10, ABHD11, ABHD12, ABHD12B, ABHD13, ABHD14A, ABHD14A-ACY1,ABHD14B, ABHD15, ABHD16A, ABHD16B, ABHD17A, ABHD17B, ABHD17C, ABHD18,ABHD2, ABHD3, ABHD4, ABHD5, ABHD6, ABHD8, ABI1, ABI2, ABI3, ABI3BP,ABL1, ABL2, ABLIM1, ABLIM2, ABLIM3, ABO, ABR, ABRA, ABRACL, ABRAXAS1,ABRAXAS2, ABT1, ABTB1, ABTB2, AC001226.2, AC002094.3, ACO002115.2,AC002310.4, AC002310.5, AC002429.2, AC002985.1, AC002996.1, ACO003002.1,AC003002.2, AC003002.3, AC003002.4, AC003005.1, AC003006.1, AC003688.1,AC004076.1, AC004080.3, AC004223.3, AC004233.2, AC004556.1, AC004691.2,AC004706.4, AC004754.1, AC004805.1, AC004832.3, AC004922.1, AC004997.1,AC005020.2, AC005041.1, ACO005154.6, AC005258.1, AC005324.3, AC005324.4,AC005520.1, AC005551.1, AC005670.2, AC005697.1, AC005702.2, AC005726.2,AC005779.2, AC005832.4, AC005833.1, AC005833.3, AC005837.2, AC005841.2,AC005885.1, AC005943.1, AC006030.1, AC006254.1, AC006269.1, AC006449.4,AC006486.1, AC006538.2, AC006978.2, AC007040.2, AC007192.1, AC007240.1,AC007325.1, AC007325.2, AC007325.4, AC007326.4, AC007375.2, AC007383.6,AC007537.5, AC007731.5, AC007906.2, AC007998.2, AC008073.3, AC008162.2,AC008393.2, AC008403.1, AC008481.3, AC008537.1, AC008560.1, AC008575.1,AC008575.2, AC008687.1, AC008687.4, AC008687.8, AC008695.1, AC008735.6,AC008750.8, AC008758.1, AC008758.4, AC008758.5, AC008758.6, AC008763.2,AC008763.3, AC008764.1, AC008764.4, AC008770.2, AC008770.3, AC008878.1,AC008878.2, AC008878.3, AC008982.1, AC008982.3, AC009014.1, AC009086.2,AC009119.2, AC009122.1, AC009133.6, AC009163.2, AC009163.4, AC009286.3,AC009336.2, AC009477.2, AC009690.1, AC009690.3, AC009779.3, AC010132.3,AC010255.3, AC010319.2, AC010323.1, AC010325.1, AC010326.2, AC010327.1,AC010422.3, AC010422.5, AC010422.6, AC010463.1, AC010487.3, AC010522.1,AC010531.1, AC010542.3, AC010547.4, AC010547.5, AC010615.4, AC010616.1,AC010619.1, AC010646.1, AC010724.2, AC011005.1, AC011043.1, AC011043.2,AC011195.2, AC011295.1, AC011346.1, AC011448.1, AC011452.1, AC011455.3,AC011455.4, AC011462.1, AC011473.4, AC011479.1, AC011498.4, AC011499.1,AC011511.1, AC011511.4, AC011530.1, AC011604.2, AC011841.1, AC012184.2,AC012254.2, AC012309.1, AC012314.1, AC012314.10, AC012314.11,AC012314.12, AC012314.4, AC012314.5, AC012314.6, AC012314.8, AC012531.3,AC012651.1, AC013269.1, AC013271.1, AC013394.1, AC013470.2, AC015688.5,AC015802.6, AC015813.2, AC017081.3, AC017081.4, AC017081.5, AC017083.4,AC018512.1, AC018523.2, AC018554.3, AC018630.6, AC018709.1, AC018755.2,AC018793.1, AC018793.2, AC018793.3, AC018793.4, AC018793.5, AC019117.3,AC020636.2, AC020909.1, AC020914.1, AC020915.1, AC020915.2, AC020915.6,AC020922.1, AC020934.3, AC021072.1, AC022016.2, AC022167.5, AC022335.1,AC022384.1, AC022400.6, AC022826.2, AC023055.1, AC023491.2, AC023509.3,AC024592.3, AC024940.1, AC024940.6, AC025165.3, AC025263.2, AC025283.2,AC025287.4, AC025594.2, AC026369.8, AC026398.1, AC026461.4, AC026464.1,AC026464.3, AC026464.4, AC026786.1, AC026954.2, AC027796.3, AC034102.2,AC036214.3, AC037459.1, AC037482.2, AC037482.3, AC040162.1, AC040162.4,AC044810.8, AC046185.1, AC048338.1, AC051649.2, AC053481.5, AC055811.2,AC058822.1, AC064853.2, AC064853.3, AC064853.4, AC064853.5, AC064853.6,AC067968.1, AC068234.1, AC068533.4, AC068547.1, AC068580.4, AC068631.2,AC068775.1, AC068775.2, AC068790.8, AC068896.1, AC068946.1, AC068987.5,AC069257.3, AC069368.1, AC069503.2, AC069544.2, AC072022.1, AC073082.1,AC073111.3, AC073111.5, AC073264.3, AC073508.2, AC073610.2, AC073610.3,AC073612.1, AC073896.1, AC074143.1, AC078927.1, AC079325.2, AC079447.1,AC079594.2, AC083800.1, AC083902.2, AC084337.2, AC087289.3, AC087498.1,AC087632.1, AC090004.1, AC090227.1, AC090360.1, AC090527.2, AC090958.3,AC091167.3, AC091167.7, AC091167.8, AC091304.7, AC091491.1, AC091551.1,AC091959.3, AC091980.2, AC092017.3, AC092042.3, AC092073.1, AC092111.3,AC092143.1, AC092329.3, AC092442.1, AC092587.1, AC092647.5, AC092718.3,AC092718.8, AC092821.1, AC092824.3, AC092835.1, AC093155.3, AC093227.3,AC093423.3, AC093525.1, AC093525.2, AC093668.1, AC093762.1, AC093762.2,AC093762.3, AC093899.2, AC096582.3, AC096887.1, AC097372.1, AC097495.1,AC097637.1, AC097662.2, AC098484.3, AC098650.1, AC098850.4, AC099329.3,AC099489.1, AC099518.3, AC099811.2, AC099850.2, AC100868.1, AC104109.3,AC104151.1, AC104304.1, AC104452.1, AC104532.1, AC104534.3, AC104581.1,AC104581.3, AC104662.2, AC104836.1, AC105001.2, AC105052.1, AC106774.10,AC106774.5, AC106774.6, AC106774.7, AC106774.8, AC106774.9, AC106782.1,AC106886.5, AC107871.1, AC108488.2, AC108750.1, AC108941.2, AC109583.3,AC110275.1, AC112229.3, AC112484.1, AC113189.6, AC113189.9, AC113331.2,AC113554.2, AC114296.1, AC114490.2, AC115220.1, AC116366.3, AC116565.1,AC117457.1, AC118470.1, AC118553.2, AC119396.1, AC119674.2, AC120057.3,AC120114.5, AC124312.1, AC126755.2, AC127537.5, AC127537.6, AC127537.8,AC129492.3, AC131097.2, AC131160.1, AC133551.1, AC133555.3, AC134669.2,AC134772.2, AC135050.2, AC135068.1, AC135068.2, AC135068.3, AC135068.8,AC135178.2, AC135586.2, AC136352.3, AC136352.4, AC136428.1, AC136612.1,AC136616.1, AC136616.2, AC136616.3, AC137834.1, AC138517.2, AC138647.1,AC138696.1, AC138811.2, AC138894.1, AC138969.1, AC139530.2, AC139677.1,AC139677.2, AC140504.1, AC141272.1, AC142391.1, AC142525.4, AC145029.2,AC145212.1, AC145212.2, AC171558.1, AC171558.3, AC171558.5, AC171558.6,AC187653.1, AC207056.1, AC209232.1, AC209539.2, AC210544.1, AC213203.1,AC229888.1, AC229888.10, AC229888.2, AC229888.3, AC229888.4, AC229888.5,AC229888.6, AC229888.7, AC229888.8, AC229888.9, AC233282.1, AC233282.2,AC233723.1, AC233724.12, AC233724.16, AC233724.17, AC233724.18,AC233724.19, AC233724.20, AC233724.21, AC233724.6, AC233755.1,AC233755.2, AC233992.2, AC234301.1, AC234301.3, AC234635.1, AC234635.3,AC234635.4, AC234635.5, AC236040.1, AC239612.1, AC239618.1, AC239618.2,AC239618.3, AC239618.4, AC239618.5, AC239618.6, AC239618.7, AC239618.9,AC239799.1, AC240274.1, AC241401.1, AC241409.2, AC241410.1, AC241556.3,AC241556.4, AC241640.1, AC241640.2, AC241640.4, AC242528.1, AC242528.2,AC243547.3, AC243733.1, AC243734.1, AC243756.1, AC243790.1, AC243967.1,AC244196.1, AC244196.2, AC244196.3, AC244196.4, AC244196.5, AC244197.3,AC244216.4, AC244216.5, AC244226.1, AC244226.2, AC244472.1, AC244472.2,AC244472.3, AC244472.4, AC244472.5, AC244489.1, AC244489.2, AC244517.10,AC244517.6, AC245033.1, AC245034.2, AC245078.1, AC245088.2, AC245088.3,AC245369.1, AC245369.2, AC245369.3, AC245369.4, AC245369.6, AC245427.1,AC245427.3, AC245427.4, AC245427.5, AC245427.6, AC245427.7, AC245427.8,AC245427.9, AC245748.1, AC247036.3, AC247036.4, AC247036.5, AC247036.6,AC254560.1, AC254788.1, AC254788.2, AC254952.1, AC255093.3, AC255093.5,AC256236.1, AC256236.2, AC256236.3, AC256300.2, AC256309.2, AC270107.1,AC270107.10, AC270107.12, AC270107.2, AC270107.3, AC270107.4,AC270107.5, AC270107.7, AC270107.8, AC270107.9, AC270227.1, AC270306.4,AC275455.2, ACAA1, ACAA2, ACACA, ACACB, ACAD10, ACAD11, ACAD8, ACAD9,ACADL, ACADM, ACADS, ACADSB, ACADVL, ACAN, ACAP1, ACAP2, ACAP3, ACAT1,ACAT2, ACBD3, ACBD4, ACBD5, ACBD6, ACBD7, ACCS, ACCSL, ACD, ACE, ACE2,ACER1, ACER2, ACER3, ACHE, ACIN1, ACKR1, ACKR2, ACKR3, ACKR4, ACLY,ACMSD, ACO1, ACO2, ACOD1, ACOT1, ACOT11, ACOT12, ACOT13, ACOT2, ACOT4,ACOT6, ACOT7, ACOT8, ACOT9, ACOX1, ACOX2, ACOX3, ACOXL, ACP1, ACP2,ACP4, ACP5, ACP6, ACP7, ACPP, ACR, ACRBP, ACRV1, ACSBG1, ACSBG2, ACSF2,ACSF3, ACSL1, ACSL3, ACSL4, ACSL5, ACSL6, ACSM1, ACSM2A, ACSM2B, ACSM3,ACSM4, ACSM5, ACSM6, ACSS1, ACSS2, ACSS3, ACTA1, ACTA2, ACTB, ACTBL2,ACTC1, ACTG1, ACTG2, ACTL10, ACTL6A, ACTL6B, ACTL7A, ACTL7B, ACTL8,ACTL9, ACTN1, ACTN2, ACTN3, ACTN4, ACTR10, ACTRIA, ACTRIB, ACTR2, ACTR3,ACTR3B, ACTR3C, ACTR5, ACTR6, ACTR8, ACTRT1, ACTRT2, ACTRT3, ACVR1,ACVR1B, ACVR1C, ACVR2A, ACVR2B, ACVRL1, ACYl, ACY3, ACYP1, ACYP2,AD000671.1, AD000671.2, ADA, ADA2, ADAD1, ADAD2, ADAL, ADAM10, ADAM11,ADAM12, ADAM15, ADAM17, ADAM18, ADAM19, ADAM2, ADAM20, ADAM21, ADAM22,ADAM23, ADAM28, ADAM29, ADAM30, ADAM32, ADAM33, ADAM7, ADAM8, ADAM9,ADAMDEC1, ADAMTS1, ADAMTS10, ADAMTS12, ADAMTS13, ADAMTS14, ADAMTS15,ADAMTS16, ADAMTS17, ADAMTS18, ADAMTS19, ADAMTS2, ADAMTS20, ADAMTS3,ADAMTS4, ADAMTS5, ADAMTS6, ADAMTS7, ADAMTS8, ADAMTS9, ADAMTSL1,ADAMTSL2, ADAMTSL3, ADAMTSL4, ADAMTSL5, ADAP1, ADAP2, ADAR, ADARBI,ADARB2, ADAT1, ADAT2, ADAT3, ADCK1, ADCK2, ADCK5, ADCY1, ADCY10, ADCY2,ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ADCYAP1, ADCYAP1R1,ADD1, ADD2, ADD3, ADGB, ADGRA1, ADGRA2, ADGRA3, ADGRB1, ADGRB2, ADGRB3,ADGRD1, ADGRD2, ADGREl, ADGRE2, ADGRE3, ADGRE5, ADGRF1, ADGRF2, ADGRF3,ADGRF4, ADGRF5, ADGRG1, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRG6, ADGRG7,ADGRL1, ADGRL2, ADGRL3, ADGRL4, ADGRV1, ADH1A, ADH1B, ADH1C, ADH4, ADH5,ADH6, ADH7, ADHFEl, ADIl, ADIG, ADIPOQ, ADIPOR1, ADIPOR2, ADIRF, ADK,ADM, ADM2, ADM5, ADNP, ADNP2, ADO, ADORA1, ADORA2A, ADORA2B, ADORA3,ADPGK, ADPRH, ADPRHL1, ADPRHL2, ADPRM, ADRA1A, ADRA1B, ADRA1D, ADRA2A,ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3, ADRM1, ADSL, ADSS, ADSSL1, ADTRP,AEBP1, AEBP2, AEN, AES, AF130351.1, AF241726.2, AFAP1, AFAP1L1, AFAP1L2,AFDN, AFF1, AFF2, AFF3, AFF4, AFG1L, AFG3L2, AFM, AFMID, AFP, AFTPH,AGA, AGAP1, AGAP2, AGAP3, AGAP4, AGAP5, AGAP6, AGAP9, AGBL1, AGBL2,AGBL3, AGBL4, AGBL5, AGER, AGFG1, AGFG2, AGGF1, AGK, AGL, AGMAT, AGMO,AGO1, AGO2, AGO3, AGO4, AGPAT1, AGPAT2, AGPAT3, AGPAT4, AGPAT5, AGPS,AGR2, AGR3, AGRN, AGRP, AGT, AGTPBP1, AGTR1, AGTR2, AGTRAP, AGXT, AGXT2,AHCTF1, AHCY, AHCYL1, AHCYL2, AHDC1, AHIl, AHNAK, AHNAK2, AHR, AHRR,AHSA1, AHSA2, AHSG, AHSP, AICDA, AIDA, AIF1, AIF1L, AIFM1, AIFM2, AIFM3,AIG1, AIM2, AIMP1, AIMP2, AIP, AIPL1, AIRE, AJAP1, AJUBA, AK1, AK2, AK3,AK4, AK5, AK6, AK7, AK8, AK9, AKAIN1, AKAP1, AKAP10, AKAP11, AKAP12,AKAP13, AKAP14, AKAP17A, AKAP2, AKAP3, AKAP4, AKAP5, AKAP6, AKAP7,AKAP8, AKAP8L, AKAP9, AKIP1, AKIRIN1, AKIRIN2, AKNA, AKNAD1, AKR1A1,AKR1B1, AKR1B10, AKR1B15, AKR1C1, AKR1C2, AKR1C3, AKR1C4, AKR1D1,AKR1E2, AKR7A2, AKR7A3, AKR7L, AKT1, AKT1S1, AKT2, AKT3, AKTIP,AL020996.2, AL021154.3, AL021546.1, AL021997.3, AL022238.4, AL022318.4,AL024498.2, ALO31708.1, AL032819.3, AL033529.1, AL035425.2, ALO35460.1,AL049634.2, AL049650.1, AL049697.1, AL049779.1, AL049839.2, AL049844.1,AL049844.3, AL080251.1, AL096814.1, AL096870.1, AL109810.2, AL109811.4,AL109827.1, AL109936.3, AL109936.4, AL110118.2, AL110118.4, AL117258.1,AL117339.5, AL117348.2, AL121581.1, AL121594.3, AL121722.1, AL121753.1,AL121758.1, AL121845.2, AL121845.3, AL132671.2, AL132780.3, AL133352.1,AL133414.1, AL133414.2, AL136295.1, AL136295.3, AL136295.4, AL136295.5,AL136373.1, AL136531.2, AL138694.1, AL138752.2, AL138826.1, AL139011.2,AL139260.3, AL139300.1, AL139353.1, AL157392.5, AL159163.1, AL160275.1,AL160276.1, AL160396.2, AL161669.4, AL161911.1, AL162231.1, AL162231.3,AL163195.3, AL163636.2, AL353572.3, AL353588.1, AL354761.2, AL354822.1,AL355102.2, AL355315.1, AL355860.1, AL355916.3, AL355987.1, AL355987.3,AL356585.9, AL357673.1, AL358075.4, AL359736.1, AL359736.3, AL359922.1,AL360181.3, AL360181.5, AL365205.1, AL365214.3, AL365232.1, AL365273.2,AL391650.1, AL449266.1, AL451007.3, AL512428.1, AL512506.3, AL512785.2,AL513165.2, AL513523.10, AL513523.9, AL583836.1, AL589666.1, AL590132.1,AL590560.1, AL591806.3, AL592183.1, AL592490.1, AL593848.2, AL603832.3,AL645922.1, AL645941.2, AL662828.1, AL662852.6, AL662899.1, AL662899.2,AL662899.3, AL669918.1, AL672043.1, AL672142.1, AL691442.1, AL713999.1,AL772284.2, AL807752.6, AL807752.7, AL844853.2, AL845331.2, AL845464.1,AL928654.4, AL929554.1, AL929561.7, ALAD, ALAS1, ALAS2, ALB, ALCAM,ALDH16A1, ALDH18A1, ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1,ALDH1L2, ALDH2, ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, ALDH4A1, ALDH5A1,ALDH6A1, ALDH7A1, ALDH8A1, ALDH9A1, ALDOA, ALDOB, ALDOC, ALG1, ALG10,ALG10B, ALG11, ALG12, ALG13, ALG14, ALG1L, ALG1L2, ALG2, ALG3, ALG5,ALG6, ALG8, ALG9, ALK, ALKALI, ALKAL2, ALKBH1, ALKBH2, ALKBH3, ALKBH4,ALKBH5, ALKBH6, ALKBH7, ALKBH8, ALLC, ALMS1, ALOX12, ALOX12B, ALOX15,ALOX15B, ALOX5, ALOX5AP, ALOXE3, ALPI, ALPK1, ALPK2, ALPK3, ALPL, ALPP,ALPPL2, ALS2, ALS2CL, ALS2CR12, ALX1, ALX3, ALX4, ALYREF, AMACR, AMBN,AMBP, AMBRA1, AMD1, AMDHD1, AMDHD2, AMELX, AMELY, AMER1, AMER2, AMER3,AMFR, AMH, AMHR2, AMIGO1, AMIGO2, AMIGO3, AMMECR1, AMMECR1L, AMN, AMN1,AMOT, AMOTL1, AMOTL2, AMPD1, AMPD2, AMPD3, AMPH, AMT, AMTN, AMY1A,AMY1B, AMY1C, AMY2A, AMY2B, AMZ1, AMZ2, ANAPC1, ANAPC10, ANAPC11,ANAPC13, ANAPC15, ANAPC16, ANAPC2, ANAPC4, ANAPC5, ANAPC7, ANG, ANGEL1,ANGEL2, ANGPT1, ANGPT2, ANGPT4, ANGPTL1, ANGPTL2, ANGPTL3, ANGPTL4,ANGPTL5, ANGPTL6, ANGPTL7, ANGPTL8, ANHX, ANK1, ANK2, ANK3, ANKAR,ANKDD1A, ANKDD1B, ANKEF1, ANKFN1, ANKFY1, ANKH, ANKHD1, ANKHD1-EIF4EBP3,ANKIB1, ANKK1, ANKLE1, ANKLE2, ANKMY1, ANKMY2, ANKRA2, ANKRD1, ANKRD10,ANKRD11, ANKRD12, ANKRD13A, ANKRD13B, ANKRD13C, ANKRD13D, ANKRD16,ANKRD17, ANKRD18A, ANKRD18B, ANKRD2, ANKRD20A1, ANKRD20A2, ANKRD20A3,ANKRD20A4, ANKRD20A8P, ANKRD22, ANKRD23, ANKRD24, ANKRD26, ANKRD27,ANKRD28, ANKRD29, ANKRD30A, ANKRD30B, ANKRD30BL, ANKRD31, ANKRD33,ANKRD33B, ANKRD34A, ANKRD34B, ANKRD34C, ANKRD35, ANKRD36, ANKRD36B,ANKRD36C, ANKRD37, ANKRD39, ANKRD40, ANKRD42, ANKRD44, ANKRD45, ANKRD46,ANKRD49, ANKRD50, ANKRD52, ANKRD53, ANKRD54, ANKRD55, ANKRD6, ANKRD60,ANKRD61, ANKRD62, ANKRD63, ANKRD65, ANKRD66, ANKRD7, ANKRD9, ANKS1A,ANKS1B, ANKS3, ANKS4B, ANKS6, ANKUB1, ANKZF1, ANLN, ANO1, ANO10, ANO2,ANO3, ANO4, ANO5, ANO6, ANO7, ANO8, ANO9, ANOS1, ANP32A, ANP32B, ANP32D,ANP32E, ANPEP, ANTXR1, ANTXR2, ANTXRL, ANXA1, ANXA10, ANXA11, ANXA13,ANXA2, ANXA2R, ANXA3, ANXA4, ANXA5, ANXA6, ANXA7, ANXA8, ANXA8L1, ANXA9,AOAH, AOC1, AOC2, AOC3, AOX1, AP000275.2, AP000295.1, AP000311.1,AP000322.1, AP000349.1, AP000350.12, AP000350.4, AP000351.3, AP000351.7,AP000721.1, AP000781.2, AP001160.5, AP001273.2, AP001458.2, AP001781.3,AP001931.1, AP002360.1, AP002373.1, AP002495.1, AP002512.3, AP002512.4,AP002748.4, AP002990.1, AP003071.5, AP003108.2, AP003419.2, AP004243.1,AP006285.3, AP1AR, AP1B1, AP1G1, AP1G2, AP1M1, AP1M2, AP1S1, AP1S2,AP1S3, AP2A1, AP2A2, AP2B1, AP2M1, AP2S1, AP3B1, AP3B2, AP3D1, AP3M1,AP3M2, AP3S1, AP3S2, AP4B1, AP4E1, AP4M1, AP4S1, AP5B1, AP5M1, AP5S1,AP5Z1, APAF1, APBA1, APBA2, APBA3, APBB1, APBBlIP, APBB2, APBB3, APC,APC2, APCDD1, APCDD1L, APCS, APEH, APELA, APEX1, APEX2, APH1A, APH1B,API5, APIP, APLF, APLN, APLNR, APLP1, APLP2, APMAP, APOA1, APOA2, APOA4,APOA5, APOB, APOBECI, APOBEC2, APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D,APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, APOBR, APOC1, APOC2, APOC3,APOC4, APOC4-APOC2, APOD, APOE, APOF, APOH, APOL1, APOL2, APOL3, APOL4,APOL5, APOL6, APOLD1, APOM, APOO, APOOL, APOPT1, APP, APPBP2, APPL1,APPL2, APRT, APTX, AQP1, AQP10, AQP11, AQP12A, AQP12B, AQP2, AQP3, AQP4,AQP5, AQP6, AQP7, AQP8, AQP9, AQR, AR, ARAF, ARAP1, ARAP2, ARAP3, ARC,ARCN1, AREG, AREL1, ARF1, ARF3, ARF4, ARF5, ARF6, ARFGAP1, ARFGAP2,ARFGAP3, ARFGEF1, ARFGEF2, ARFGEF3, ARFIP1, ARFIP2, ARFRP1, ARG1, ARG2,ARGFX, ARGLU1, ARHGAP1, ARHGAP10, ARHGAP11 A, ARHGAP11B, ARHGAP12,ARHGAP15, ARHGAP17, ARHGAP18, ARHGAP19, ARHGAP19-SLIT1, ARHGAP20,ARHGAP21, ARHGAP22, ARHGAP23, ARHGAP24, ARHGAP25, ARHGAP26, ARHGAP27,ARHGAP28, ARHGAP29, ARHGAP30, ARHGAP31, ARHGAP32, ARHGAP33, ARHGAP35,ARHGAP36, ARHGAP39, ARHGAP4, ARHGAP40, ARHGAP42, ARHGAP44, ARHGAP45,ARHGAP5, ARHGAP6, ARHGAP8, ARHGAP9, ARHGDIA, ARHGDIB, ARHGDIG, ARHGEF1,ARHGEF10, ARHGEF10L, ARHGEF11, ARHGEF12, ARHGEF15, ARHGEF16, ARHGEF17,ARHGEF18, ARHGEF19, ARHGEF2, ARHGEF25, ARHGEF26, ARHGEF28, ARHGEF3,ARHGEF33, ARHGEF35, ARHGEF37, ARHGEF38, ARHGEF39, ARHGEF4, ARHGEF40,ARHGEF5, ARHGEF6, ARHGEF7, ARHGEF9, ARID1A, ARIDIB, ARID2, ARID3A,ARID3B, ARID3C, ARID4A, ARID4B, ARID5A, ARID5B, ARIH1, ARIH2, ARIH2OS,ARL1, ARL10, ARL11, ARL13A, ARL13B, ARL14, ARL14EP, ARL14EPL, ARL15,ARL16, ARL17A, ARL17B, ARL2, ARL2BP, ARL2-SNX15, ARL3, ARL4A, ARL4C,ARL4D, ARL5A, ARL5B, ARL5C, ARL6, ARL6IP1, ARL6IP4, ARL6IP5, ARL6IP6,ARL8A, ARL8B, ARL9, ARMC1, ARMC10, ARMC12, ARMC2, ARMC3, ARMC4, ARMC5,ARMC6, ARMC7, ARMC8, ARMC9, ARMCX1, ARMCX2, ARMCX3, ARMCX4, ARMCX5,ARMCX6, ARMS2, ARMT1, ARNT, ARNT2, ARNTL, ARNTL2, ARPC1A, ARPCIB, ARPC2,ARPC3, ARPC4, ARPC4-TTLL3, ARPC5, ARPC5L, ARPIN, ARPP19, ARPP21, ARR3,ARRB1, ARRB2, ARRDC1, ARRDC2, ARRDC3, ARRDC4, ARRDC5, ARSA, ARSB, ARSD,ARSE, ARSF, ARSG, ARSH, ARSI, ARSJ, ARSK, ART1, ART3, ART4, ART5, ARTN,ARV1, ARVCF, ARX, AS3MT, ASAH1, ASAH2, ASAH2B, ASAP1, ASAP2, ASAP3,ASB1, ASB10, ASB11, ASB12, ASB13, ASB14, ASB15, ASB16, ASB17, ASB18,ASB2, ASB3, ASB4, ASB5, ASB6, ASB7, ASB8, ASB9, ASCC1, ASCC2, ASCC3,ASCL1, ASCL2, ASCL3, ASCL4, ASCL5, ASF1A, ASF1B, ASGR1, ASGR2, ASH1L,ASH2L, ASIC1, ASIC2, ASIC3, ASIC4, ASIC5, ASIP, ASL, ASMT, ASMTL, ASNA1,ASNS, ASNSD1, ASPA, ASPDH, ASPG, ASPH, ASPHDI, ASPHD2, ASPM, ASPN,ASPRV1, ASPSCR1, ASRGL1, ASS1, ASTE1, ASTL, ASTN1, ASTN2, ASXL1, ASXL2,ASXL3, ASZ1, ATAD1, ATAD2, ATAD2B, ATAD3A, ATAD3B, ATAD3C, ATAD5, ATAT1,ATCAY, ATE1, ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, ATF6B, ATF7, ATF7IP,ATF7IP2, ATG10, ATG101, ATG12, ATG13, ATG14, ATG16L1, ATG16L2, ATG2A,ATG2B, ATG3, ATG4A, ATG4B, ATG4C, ATG4D, ATG5, ATG7, ATG9A, ATG9B, ATIC,ATL1, ATL2, ATL3, ATM, ATMIN, ATN1, ATOH1, ATOH7, ATOH8, ATOX1, ATP10A,ATP10B, ATP10D, ATP11A, ATP11B, ATP11C, ATP12A, ATP13A1, ATP13A2,ATP13A3, ATP13A4, ATP13A5, ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B1,ATP1B2, ATP1B3, ATP1B4, ATP23, ATP2A1, ATP2A2, ATP2A3, ATP2B1, ATP2B2,ATP2B3, ATP2B4, ATP2C1, ATP2C2, ATP4A, ATP4B, ATP5A1, ATP5B, ATP5C1,ATP5D, ATP5E, ATP5EP2, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5H, ATP5I,ATP5J, ATP5J2, ATP5J2-PTCD1, ATP5L, ATP5L2, ATP50, ATP5S, ATP6AP1,ATP6AP1L, ATP6AP2, ATP6VOA1, ATP6VOA2, ATP6VOA4, ATP6VOB, ATP6VOC,ATP6VOD1, ATP6VOD2, ATP6VOE1, ATP6VOE2, ATP6V1A, ATP6V1B1, ATP6V1B2,ATP6V1C1, ATP6V1C2, ATP6V1D, ATP6V1E1, ATP6V1E2, ATP6V1F, ATP6V1G1,ATP6V1G2, ATP6V1G2-DDX39B, ATP6V1G3, ATP6V1H, ATP7A, ATP7B, ATP8A1,ATP8A2, ATP8B1, ATP8B2, ATP8B3, ATP8B4, ATP9A, ATP9B, ATPAF1, ATPAF2,ATPIF1, ATR, ATRAID, ATRIP, ATRN, ATRNL1, ATRX, ATXN1, ATXN10, ATXN1L,ATXN2, ATXN2L, ATXN3, ATXN3L, ATXN7, ATXN7L1, ATXN7L2, ATXN7L3,ATXN7L3B, AUH, AUNIP, AUP1, AURKA, AURKAIP1, AURKB, AURKC, AUTS2, AVEN,AVIL, AVL9, AVP, AVPI1, AVPR1A, AVPR1B, AVPR2, AWAT1, AWAT2, AXDND1,AXIN1, AXIN2, AXL, AZGP1, AZI2, AZIN1, AZIN2, AZUl, B2M, B3GALNT1,B3GALNT2, B3GALT1, B3GALT2, B3GALT4, B3GALT5, B3GALT6, B3GAT1, B3GAT2,B3GAT3, B3GLCT, B3GNT2, B3GNT3, B3GNT4, B3GNT5, B3GNT6, B3GNT7, B3GNT8,B3GNT9, B3GNTL1, B4GALNT1, B4GALNT2, B4GALNT3, B4GALNT4, B4GALT1,B4GALT2, B4GALT3, B4GALT4, B4GALT5, B4GALT6, B4GALT7, B4GAT1, B9D1,B9D2, BAALC, BAAT, BABAMI, BABAM2, BACE1, BACE2, BACH1, BACH2, BAD,BAG1, BAG2, BAG3, BAG4, BAG5, BAG6, BAGE3, BAHCC1, BAHD1, BAIAP2,BAIAP2L1, BAIAP2L2, BAIAP3, BAK1, BAMBI, BANF1, BANF2, BANK1, BANP,BAP1, BARD1, BARHL1, BARHL2, BARX1, BARX2, BASP1, BATF, BATF2, BATF3,BAX, BAZ1A, BAZ1B, BAZ2A, BAZ2B, BBC3, BBIP1, BBOF1, BBOX1, BBS1, BBS10,BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BBX, BCAM, BCAN, BCAP29, BCAP31,BCAR1, BCAR3, BCAS1, BCAS2, BCAS3, BCAS4, BCAT1, BCAT2, BCCIP, BCDIN3D,BCHE, BCKDHA, BCKDHB, BCKDK, BCL10, BCL11A, BCL11B, BCL2, BCL2A1,BCL2L1, BCL2L10, BCL2L11, BCL2L12, BCL2L13, BCL2L14, BCL2L15, BCL2L2,BCL2L2-PABPN1, BCL3, BCL6, BCL6B, BCL7A, BCL7B, BCL7C, BCL9, BCL9L,BCLAF1, BCLAF3, BCO1, BCO2, BCOR, BCORL1, BCR, BCS1L, BDH1, BDH2,BDKRB1, BDKRB2, BDNF, BDP1, BEAN1, BECN1, BECN2, BEGAIN, BEND2, BEND3,BEND4, BEND5, BEND6, BEND7, BEST1, BEST2, BEST3, BEST4, BET1, BET1L,BEX1, BEX2, BEX3, BEX4, BEX5, BFAR, BFSP1, BFSP2, BGLAP, BGN, BHLHA15,BHLHA9, BHLHB9, BHLHE22, BHLHE23, BHLHE40, BHLHE41, BHMG1, BHMT, BHMT2,BICC1, BICD1, BICD2, BICDL1, BICDL2, BICRA, BICRAL, BID, BIK, BIN1,BIN2, BIN3, BIRC2, BIRC3, BIRC5, BIRC6, BIRC7, BIRC8, BIVM, BIVM-ERCC5,BLACE, BLCAP, BLID, BLK, BLM, BLMH, BLNK, BLOC1S1, BLOC1S2, BLOC1S3,BLOC1S4, BLOC1S5, BLOC1S5-TXNDC5, BLOC1S6, BLVRA, BLVRB, BLZF1, BMF,BMI1, BMP1, BMP10, BMP15, BMP2, BMP2K, BMP3, BMP4, BMP5, BMP6, BMP7,BMP8A, BMP8B, BMPER, BMPR1A, BMPR1B, BMPR2, BMS1, BMT2, BMX, BNC1, BNC2,BNIP1, BNIP2, BNIP3, BNIP3L, BNIPL, BOC, BOD1, BOD1L1, BOD1L2, BOK,BOLA1, BOLA2, BOLA2B, BOLA2-SMG1P6, BOLA3, BOLL, BOP1, BORA, BORCS5,BORCS6, BORCS7, BORCS7-ASMT, BORCS8, BORCS8-MEF2B, BPGM, BPHL, BPI,BPIFA1, BPIFA2, BPIFA3, BPIFB1, BPIFB2, BPIFB3, BPIFB4, BPIFB6, BPIFC,BPNT1, BPTF, BPY2, BPY2B, BPY2C, BRAF, BRAP, BRAT1, BRCA1, BRCA2, BRCC3,BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9, BRDT, BRF1, BRF2, BRI3,BRI3BP, BRICD5, BRINPI, BRINP2, BRINP3, BRIP1, BRIX1, BRK1, BRMS1,BRMS1L, BROX, BRPF1, BRPF3, BRS3, BRSK1, BRSK2, BRWD1, BRWD3, BSCL2,BSDC1, BSG, BSN, BSND, BSPH1, BSPRY, BST1, BST2, BSX, BTAF1, BTBD1,BTBD10, BTBD11, BTBD16, BTBD17, BTBD18, BTBD19, BTBD2, BTBD3, BTBD6,BTBD7, BTBD8, BTBD9, BTC, BTD, BTF3, BTF3L4, BTG1, BTG2, BTG3, BTG4,BTK, BTLA, BTN1A1, BTN2A1, BTN2A2, BTN3A1, BTN3A2, BTN3A3, BTNL2, BTNL3,BTNL8, BTNL9, BTRC, BUB1, BUB1B, BUB1B-PAK6, BUB3, BUD13, BUD23, BUD31,B VES, BX004987.1, BX072566.1, BX088645.1, BX248244.1, BX248413.4,BX248415.1, BX248516.1, BX276092.9, BYSL, BZW1, BZW2, C10orf10,C10orf105, C10orf107, C10orf113, C10orf120, C10orf126, C10orf128,C10orf142, C10orf35, C10orf53, C10orf55, C10orf62, C10orf67, C10orf71,C10orf76, C10orf82, C10orf88, C10orf90, C10orf95, C10orf99, C11orf1,C11orf16, C11orf21, C11orf24, C11orf40, C11orf42, C11orf45, C11orf49,C11orf52, C11orf53, C11orf54, C11orf57, C11orf58, C11orf63, C11orf65,C11orf68, C11orf70, C11orf71, C11orf74, C11orf80, C11orf84, C11orf86,C11orf87, C11orf88, C11orf91, C11orf94, C11orf95, C11orf96, C11orf97,C11orf98, C12orf10, C12orf29, C12orf4, C12orf40, C12orf42, C12orf43,C12orf45, C12orf49, C12orf50, C12orf54, C12orf56, C12orf57, C12orf60,C12orf65, C12orf66, C12orf71, C12orf73, C12orf74, C12orf75, C12orf76,C13orf42, C14orf105, C14orf119, C14orf132, C14orf159, C14orf166,C14orf177, C14orf178, C14orf180, C14orf2, C14orf28, C14orf37, C14orf39,C14orf79, C14orf80, C14orf93, C15orf38-AP3S2, C15orf39, C15orf40,C15orf41, C15orf48, C15orf52, C15orf53, C15orf59, C15orf61, C15orf62,C15orf65, C16orf45, C16orf46, C16orf52, C16orf54, C16orf58, C16orf59,C16orf62, C16orf70, C16orf71, C16orf72, C16orf74, C16orf78, C16orf82,C16orf86, C16orf87, C16orf89, C16orf90, C16orf91, C16orf92, C16orf95,C16orf96, C17orf100, C17orf105, C17orf107, C17orf113, C17orf47,C17orf49, C17orf50, C17orf51, C17orf53, C17orf58, C17orf62, C17orf64,C17orf67, C17orf74, C17orf75, C17orf78, C17orf80, C17orf97, C17orf98,C17orf99, C18orf21, C18orf25, C18orf32, C18orf54, C18orf63, C18orf8,C19orf12, C19orf18, C19orf24, C19orf25, C19orf33, C19orf35, C19orf38,C19orf44, C19orf47, C19orf48, C19orf53, C19orf54, C19orf57, C19orf60,C19orf66, C19orf67, C19orf68, C19orf70, C19orf71, C19orf73, C19orf81,C19orf84, C1D, C1GALT1, C1GALT1C1, C1GALT1C1L, C1orf100, C1orf105,C1orf109, C1orf112, C1orf115, C1orf116, C1orf122, C1orf123, C1orf127,C1orf131, C1orf141, C1orf146, C1orf158, C1orf159, C1orf162, C1orf167,C1orf174, C1orf185, C1orf186, C1orf189, C1orf194, C1orf198, C1orf21,C1orf210, C1orf216, C1orf226, C1orf228, C1orf232, C1orf27, C1orf35,C1orf43, C1orf50, C1orf52, C1orf53, C1orf54, C1orf56, C1orf61, C1orf64,C1orf68, C1orf74, C1orf87, C1orf94, C1QA, C1QB, C1QBP, C1QC, C1QL1,C1QL2, C1QL3, C1QL4, C1QTNF1, C1QTNF12, C1QTNF2, C1QTNF3, C1QTNF3-AMACR,ClQTNF4, C1QTNF5, C1QTNF6, C1QTNF7, C1QTNF8, C1QTNF9, C1QTNF9B, C1R,C1RL, C1S, C2, C20orf141, C20orf144, C20orf173, C20orf194, C20orf196,C20orf202, C20orf204, C20orf24, C20orf27, C20orf85, C20orf96, C21orf140,C21orf2, C21orf33, C21orf58, C21orf59, C21orf62, C21orf91, C22orf15,C22orf23, C22orf31, C22orf39, C22orf42, C22orf46, C2CD2, C2CD2L, C2CD3,C2CD4A, C2CD4B, C2CD4C, C2CD4D, C2CD5, C2CD6, C2orf15, C2orf16, C2orf40,C2orf42, C2orf49, C2orf50, C2orf54, C2orf66, C2orf68, C2orf69, C2orf70,C2orf71, C2orf72, C2orf73, C2orf74, C2orf76, C2orf78, C2orf80, C2orf81,C2orf82, C2orf83, C2orf88, C2orf91, C3, C3AR1, C3orf14, C3orf18,C3orf20, C3orf22, C3orf30, C3orf33, C3orf35, C3orf36, C3orf38, C3orf49,C3orf52, C3orf56, C3orf58, C3orf62, C3orf67, C3orf70, C3orf80, C3orf84,C3orf85, C4A, C4B, C4B2, C4BPA, C4BPB, C4orf17, C4orf19, C4orf22,C4orf26, C4orf3, C4orf32, C4orf33, C4orf36, C4orf45, C4orf46, C4orf47,C4orf48, C4orf50, C4orf51, C5, C5AR1, C5AR2, C5orf15, C5orf22, C5orf24,C5orf30, C5orf34, C5orf38, C5orf42, C5orf46, C5orf47, C5orf49, C5orf51,C5orf52, C5orf56, C5orf58, C5orf60, C5orf63, C5orf67, C6, C6orf10,C6orf106, C6orf118, C6orf120, C6orf132, C6orf136, C6orf141, C6orf15,C6orf163, C6orf201, C6orf203, C6orf222, C6orf223, C6orf226, C6orf229,C6orf47, C6orf48, C6orf52, C6orf58, C6orf62, C6orf89, C7, C7orf25,C7orf26, C7orf31, C7orf33, C7orf34, C7orf43, C7orf49, C7orf50,C7orf55-LUC7L2, C7orf57, C7orf61, C7orf72, C7orf73, C7orf77, C8A, C8B,C8G, C8orf22, C8orf33, C8orf34, C8orf37, C8orf4, C8orf44, C8orf44-SGK3,C8orf46, C8orf48, C8orf58, C8orf59, C8orf74, C8orf76, C8orf82, C8orf86,C8orf88, C8orf89, C9, C9orf116, C9orf129, C9orf131, C9orf135, C9orf152,C9orf153, C9orf16, C9orf172, C9orf24, C9orf3, C9orf40, C9orf43, C9orf47,C9orf50, C9orf57, C9orf64, C9orf66, C9orf72, C9orf78, C9orf84, C9orf85,C9orf92, CA1, CA10, CA11, CA12, CA13, CA14, CA2, CA3, CA4, CA5A, CA5B,CA6, CA7, CA8, CA9, CAAP1, CAB39, CAB39L, CABIN1, CABLES1, CABLES2,CABP1, CABP2, CABP4, CABP5, CABP7, CABS1, CABYR, CACFD1, CACHD1,CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H,CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1,CACNB2, CACNB3, CACNB4, CACNG1, CACNG2, CACNG3, CACNG4, CACNG5, CACNG6,CACNG7, CACNG8, CACTIN, CACUL1, CACYBP, CAD, CADM1, CADM2, CADM3, CADM4,CADPS, CADPS2, CAGE1, CALB1, CALB2, CALCA, CALCB, CALCOCO1, CALCOCO2,CALCR, CALCRL, CALD1, CALHMI, CALHM2, CALHM3, CALM1, CALM2, CALM3,CALML3, CALML4, CALML5, CALML6, CALN1, CALR, CALR3, CALU, CALY, CAMK1,CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CAMK2N1, CAMK2N2, CAMK4,CAMKK1, CAMKK2, CAMKMT, CAMKV, CAMLG, CAMP, CAMSAP1, CAMSAP2, CAMSAP3,CAMTA1, CAMTA2, CAND1, CAND2, CANT1, CANX, CAP1, CAP2, CAPG, CAPN1,CAPN10, CAPN11, CAPN12, CAPN13, CAPN14, CAPN15, CAPN2, CAPN3, CAPN5,CAPN6, CAPN7, CAPN8, CAPN9, CAPNS1, CAPNS2, CAPRIN1, CAPRIN2, CAPS,CAPS2, CAPSL, CAPZA1, CAPZA2, CAPZA3, CAPZB, CARD10, CARD11, CARD14,CARD16, CARD17, CARD18, CARD19, CARD6, CARD8, CARD9, CARF, CARHSP1,CARM1, CARMIL1, CARMIL2, CARMIL3, CARNMT1, CARNS1, CARS, CARS2, CARTPT,CASC1, CASC10, CASC3, CASC4, CASD1, CASK, CASKINI, CASKIN2, CASP1,CASP10, CASP12, CASP14, CASP2, CASP3, CASP4, CASP5, CASP6, CASP7, CASP8,CASP8AP2, CASP9, CASQ1, CASQ2, CASR, CASS4, CAST, CASTORI, CASTOR2,CASZ1, CAT, CATIP, CATSPER1, CATSPER2, CATSPER3, CATSPER4, CATSPERB,CATSPERD, CATSPERE, CATSPERG, CATSPERZ, CAV1, CAV2, CAV3, CAVIN1,CAVIN2, CAVIN3, CAVIN4, CBARP, CBFA2T2, CBFA2T3, CBFB, CBL, CBLB, CBLC,CBLL1, CBLN1, CBLN2, CBLN3, CBLN4, CBR1, CBR3, CBR4, CBS, CBSL, CBWD1,CBWD2, CBWD3, CBWD5, CBWD6, CBX1, CBX2, CBX3, CBX4, CBX5, CBX6, CBX7,CBX8, CBY1, CBY3, CC2D1A, CC2D1B, CC2D2A, CC2D2B, CCAR1, CCAR2, CCBE1,CCDC102A, CCDC102B, CCDC103, CCDC105, CCDC106, CCDC107, CCDC110,CCDC112, CCDC113, CCDC114, CCDC115, CCDC116, CCDC117, CCDC12, CCDC120,CCDC121, CCDC122, CCDC124, CCDC125, CCDC126, CCDC127, CCDC129, CCDC13,CCDC130, CCDC134, CCDC136, CCDC137, CCDC138, CCDC14, CCDC140, CCDC141,CCDC142, CCDC144A, CCDC144NL, CCDC146, CCDC148, CCDC149, CCDC15,CCDC150, CCDC151, CCDC152, CCDC153, CCDC154, CCDC155, CCDC157, CCDC158,CCDC159, CCDC160, CCDC163, CCDC166, CCDC167, CCDC168, CCDC169,CCDC169-SOHLH2, CCDC17, CCDC170, CCDC171, CCDC172, CCDC173, CCDC174,CCDC175, CCDC177, CCDC178, CCDC179, CCDC18, CCDC180, CCDC181, CCDC182,CCDC183, CCDC184, CCDC185, CCDC186, CCDC187, CCDC188, CCDC189, CCDC190,CCDC191, CCDC192, CCDC194, CCDC195, CCDC196, CCDC197, CCDC22, CCDC24,CCDC25, CCDC27, CCDC28A, CCDC28B, CCDC3, CCDC30, CCDC32, CCDC33, CCDC34,CCDC36, CCDC38, CCDC39, CCDC40, CCDC42, CCDC43, CCDC47, CCDC50, CCDC51,CCDC54, CCDC57, CCDC58, CCDC59, CCDC6, CCDC60, CCDC61, CCDC62, CCDC63,CCDC65, CCDC66, CCDC68, CCDC69, CCDC7, CCDC70, CCDC71, CCDC71L, CCDC73,CCDC74A, CCDC74B, CCDC77, CCDC78, CCDC8, CCDC80, CCDC81, CCDC82, CCDC83,CCDC84, CCDC85A, CCDC85B, CCDC85C, CCDC86, CCDC87, CCDC88A, CCDC88B,CCDC88C, CCDC89, CCDC9, CCDC90B, CCDC91, CCDC92, CCDC93, CCDC94, CCDC96,CCDC97, CCER1, CCER2, CCHCR1, CCIN, CCK, CCKAR, CCKBR, CCL1, CCL11,CCL13, CCL14, CCL15, CCL15-CCL14, CCL16, CCL17, CCL18, CCL19, CCL2,CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3,CCL3L1, CCL3L3, CCL4, CCL4L2, CCL5, CCL7, CCL8, CCM2, CCM2L, CCNA1,CCNA2, CCNB1, CCNB1IP1, CCNB2, CCNB3, CCNC, CCND1, CCND2, CCND3,CCNDBP1, CCNE1, CCNE2, CCNF, CCNG1, CCNG2, CCNH, CCNI, CCNI2, CCNJ,CCNJL, CCNK, CCNL1, CCNL2, CCNO, CCNT1, CCNT2, CCNY, CCNYL1, CCP110,CCPG1, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9,CCRL2, CCS, CCSAP, CCSER1, CCSER2, CCT2, CCT3, CCT4, CCT5, CCT6A, CCT6B,CCT7, CCT8, CCT8L2, CCZ1, CCZ1B, CD101, CD109, CD14, CD151, CD160,CD163, CD163L1, CD164, CD164L2, CD177, CD180, CD19, CD1A, CD1B, CD1C,CD1D, CD1E, CD2, CD200, CD200R1, CD200R1L, CD207, CD209, CD22, CD226,CD24, CD244, CD247, CD248, CD27, CD274, CD276, CD28, CD2AP, CD2BP2,CD300A, CD300C, CD300E, CD300LB, CD300LD, CD300LF, CD300LG, CD302,CD320, CD33, CD34, CD36, CD37, CD38, CD3D, CD3E, CD3EAP, CD3G, CD4,CD40, CD40LG, CD44, CD46, CD47, CD48, CD5, CD52, CD53, CD55, CD58, CD59,CD5L, CD6, CD63, CD68, CD69, CD7, CD70, CD72, CD74, CD79A, CD79B, CD80,CD81, CD82, CD83, CD84, CD86, CD8A, CD8B, CD9, CD93, CD96, CD99, CD99L2,CDA, CDADC1, CDAN1, CDC123, CDC14A, CDC14B, CDC16, CDC20, CDC20B, CDC23,CDC25A, CDC25B, CDC25C, CDC26, CDC27, CDC34, CDC37, CDC37L1, CDC40,CDC42, CDC42BPA, CDC42BPB, CDC42BPG, CDC42EP1, CDC42EP2, CDC42EP3,CDC42EP4, CDC42EP5, CDC42SE1, CDC42SE2, CDC45, CDC5L, CDC6, CDC7, CDC73,CDCA2, CDCA3, CDCA4, CDCA5, CDCA7, CDCA7L, CDCA8, CDCP1, CDCP2, CDH1,CDH10, CDH11, CDH12, CDH13, CDH15, CDH16, CDH17, CDH18, CDH19, CDH2,CDH20, CDH22, CDH23, CDH24, CDH26, CDH3, CDH4, CDH5, CDH6, CDH7, CDH8,CDH9, CDHR1, CDHR2, CDHR3, CDHR4, CDHR5, CDIP1, CDIPT, CDK1, CDK10,CDK11A, CDK11B, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19,CDK2, CDK20, CDK2AP1, CDK2AP2, CDK3, CDK4, CDK5, CDK5R1, CDK5R2,CDK5RAP1, CDK5RAP2, CDK5RAP3, CDK6, CDK7, CDK8, CDK9, CDKAL1, CDKL1,CDKL2, CDKL3, CDKL4, CDKL5, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2AIP,CDKN2AIPNL, CDKN2B, CDKN2C, CDKN2D, CDKN3, CDNF, CDO1, CDON, CDPF1,CDR1, CDR2, CDR2L, CDRT1, CDRT15, CDRT15L2, CDRT4, CDS1, CDS2, CDSN,CDT1, CDV3, CDX1, CDX2, CDX4, CDY1, CDY1B, CDY2A, CDY2B, CDYL, CDYL2,CEACAMI, CEACAM16, CEACAM19, CEACAM20, CEACAM21, CEACAM3, CEACAM4,CEACAM5, CEACAM6, CEACAM7, CEACAM8, CEBPA, CEBPB, CEBPD, CEBPE, CEBPG,CEBPZ, CEBPZOS, CECR2, CEL, CELAl, CELA2A, CELA2B, CELA3A, CELA3B,CELF1, CELF2, CELF3, CELF4, CELF5, CELF6, CELSR1, CELSR2, CELSR3, CEMIP,CEMP1, CEND1, CENPA, CENPB, CENPBD1, CENPC, CENPE, CENPF, CENPH, CENPI,CENPJ, CENPK, CENPL, CENPM, CENPN, CENPO, CENPP, CENPQ, CENPS,CENPS-CORT, CENPT, CENPU, CENPV, CENPVL1, CENPVL2, CENPVL3, CENPW,CENPX, CEP104, CEP112, CEP120, CEP126, CEP128, CEP131, CEP135, CEP152,CEP162, CEP164, CEP170, CEP170B, CEP19, CEP192, CEP250, CEP290, CEP295,CEP295NL, CEP350, CEP41, CEP44, CEP55, CEP57, CEP57L1, CEP63, CEP68,CEP70, CEP72, CEP76, CEP78, CEP83, CEP85, CEP85L, CEP89, CEP95, CEP97,CEPT1, CER1, CERCAM, CERK, CERKL, CERS1, CERS2, CERS3, CERS4, CERS5,CERS6, CES1, CES2, CES3, CES4A, CESSA, CETN1, CETN2, CETN3, CETP,CFAP100, CFAP126, CFAP157, CFAP161, CFAP20, CFAP206, CFAP221, CFAP36,CFAP43, CFAP44, CFAP45, CFAP46, CFAP47, CFAP52, CFAP53, CFAP54, CFAP57,CFAP58, CFAP61, CFAP65, CFAP69, CFAP70, CFAP73, CFAP74, CFAP77, CFAP97,CFAP99, CFB, CFC1, CFC1B, CFD, CFDP1, CFH, CFHR1, CFHR2, CFHR3, CFHR4,CFHR5, CFI, CFL1, CFL2, CFLAR, CFP, CFTR, CGA, CGB1, CGB2, CGB3, CGB5,CGB7, CGB8, CGGBP1, CGN, CGNL1, CGREF1, CGRRF1, CH25H, CHAC1, CHAC2,CHAD, CHADL, CHAF1A, CHAFlB, CHAMP1, CHAT, CHCHD1, CHCHD10, CHCHD2,CHCHD3, CHCHD4, CHCHD5, CHCHD6, CHCHD7, CHD1, CHD1L, CHD2, CHD3, CHD4,CHD5, CHD6, CHD7, CHD8, CHD9, CHDH, CHEK1, CHEK2, CHERP, CHFR, CHGA,CHGB, CHI3L1, CHI3L2, CHIA, CHIC1, CHIC2, CHID1, CHIT1, CHKA, CHKB,CHKB-CPT1B, CHL1, CHM, CHML, CHMPlA, CHMPIB, CHMP2A, CHMP2B, CHMP3,CHMP4A, CHMP4B, CHMP4C, CHMP5, CHMP6, CHMP7, CHN1, CHN2, CHODL, CHORDC1,CHP1, CHP2, CHPF, CHPF2, CHPT1, CHRACI, CHRD, CHRDLI, CHRDL2, CHRFAM7A,CHRM1, CHRM2, CHRM3, CHRM4, CHRM5, CHRNA1, CHRNA10, CHRNA2, CHRNA3,CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB2, CHRNB3, CHRNB4,CHRND, CHRNE, CHRNG, CHST1, CHST10, CHST11, CHST12, CHST13, CHST14,CHST15, CHST2, CHST3, CHST4, CHST5, CHST6, CHST7, CHST8, CHST9, CHSY1,CHSY3, CHTF18, CHTF8, CHTOP, CHUK, CHURC1, CHURC1-FNTB, CIAO1, CIAPIN1,CIART, CIB1, CIB2, CIB3, CIB4, CIC, CIDEA, CIDEB, CIDEC, CIITA, CILP,CILP2, CINP, CIPC, CIR1, CIRBP, CISD1, CISD2, CISD3, CISH, CIT, CITED1,CITED2, CITED4, CIZ1, CKAP2, CKAP2L, CKAP4, CKAP5, CKB, CKLF,CKLF-CMTM1, CKM, CKMT1A, CKMTlB, CKMT2, CKS1B, CKS2, CLASPI, CLASP2,CLASRP, CLC, CLCA1, CLCA2, CLCA4, CLCC1, CLCF1, CLCN1, CLCN2, CLCN3,CLCN4, CLCN5, CLCN6, CLCN7, CLCNKA, CLCNKB, CLDN1, CLDN10, CLDN11,CLDN12, CLDN14, CLDN15, CLDN16, CLDN17, CLDN18, CLDN19, CLDN2, CLDN20,CLDN22, CLDN23, CLDN24, CLDN25, CLDN3, CLDN34, CLDN4, CLDN5, CLDN6,CLDN7, CLDN8, CLDN9, CLDND1, CLDND2, CLEC10A, CLEC11A, CLEC12A, CLEC12B,CLEC14A, CLEC16A, CLEC17A, CLEC18A, CLEC18B, CLEC18C, CLEC19A, CLEC1A,CLECIB, CLEC20A, CLEC2A, CLEC2B, CLEC2D, CLEC2L, CLEC3A, CLEC3B, CLEC4A,CLEC4C, CLEC4D, CLEC4E, CLEC4F, CLEC4G, CLEC4M, CLEC5A, CLEC6A, CLEC7A,CLEC9A, CLECL1, CLGN, CLHC1, CLIC1, CLIC2, CLIC3, CLIC4, CLIC5, CLIC6,CLINT1, CLIP1, CLIP2, CLIP3, CLIP4, CLK1, CLK2, CLK3, CLK4, CLLU1,CLLU1OS, CLMN, CLMP, CLN3, CLN5, CLN6, CLN8, CLNK, CLNS1A, CLOCK, CLP1,CLPB, CLPP, CLPS, CLPSL1, CLPSL2, CLPTM1, CLPTM1L, CLPX, CLRN1, CLRN2,CLRN3, CLSPN, CLSTN1, CLSTN2, CLSTN3, CLTA, CLTB, CLTC, CLTCL1, CLU,CLUAPI, CLUH, CLUL1, CLVS1, CLVS2, CLYBL, CMA1, CMAS, CMBL, CMC1, CMC2,CMC4, CMIP, CMKLR1, CMPK1, CMPK2, CMSS1, CMTM1, CMTM2, CMTM3, CMTM4,CMTM5, CMTM6, CMTM7, CMTM8, CMTR1, CMTR2, CMYA5, CNBD1, CNBD2, CNBP,CNDP1, CNDP2, CNEP1R1, CNFN, CNGA1, CNGA2, CNGA3, CNGA4, CNGB1, CNGB3,CNIH1, CNIH2, CNIH3, CNIH4, CNKSR1, CNKSR2, CNKSR3, CNMD, CNN1, CNN2,CNN3, CNNM1, CNNM2, CNNM3, CNNM4, CNOT1, CNOT10, CNOT11, CNOT2, CNOT3,CNOT4, CNOT6, CNOT6L, CNOT7, CNOT8, CNOT9, CNP, CNPPD1, CNPY1, CNPY2,CNPY3, CNPY4, CNR1, CNR2, CNRIP1, CNST, CNTD1, CNTD2, CNTF, CNTFR,CNTLN, CNTN1, CNTN2, CNTN3, CNTN4, CNTN5, CNTN6, CNTNAP1, CNTNAP2,CNTNAP3, CNTNAP3B, CNTNAP4, CNTNAP5, CNTRL, CNTROB, COAl, COA3, COA4,COA5, COA6, COA7, COASY, COBL, COBLL1, COCH, COG1, COG2, COG3, COG4,COG5, COG6, COG7, COG8, COIL, COL10A1, COL11A1, COL11A2, COL12A1,COL13A1, COL14A1, COL15A1, COL16A1, COL17A1, COL18A1, COL19A1, COL1A1,COL1A2, COL20A1, COL21A1, COL22A1, COL23A1, COL24A1, COL25A1, COL26A1,COL27A1, COL28A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A3BP,COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, COL6A3,COL6A5, COL6A6, COL7A1, COL8A1, COL8A2, COL9A1, COL9A2, COL9A3, COLCA2,COLEC10, COLEC11, COLEC12, COLGALT1, COLGALT2, COLQ, COMMD1, COMMD10,COMMD2, COMMD3, COMMD3-BMI1, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8,COMMD9, COMP, COMT, COMTD1, COPA, COPB1, COPB2, COPE, COPG1, COPG2,COPRS, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7A, COPS7B, COPS8, COPS9,COPZ1, COPZ2, COQ10A, COQ10B, COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, COQ8A,COQ8B, COQ9, CORIN, CORO1A, COROIB, COROIC, CORO2A, CORO2B, CORO6,CORO7, CORO7-PAM16, CORT, COTL1, COX10, COX11, COX14, COX15, COX16,COX17, COX18, COX19, COX20, COX4I1, COX4I2, COX5A, COX5B, COX6A1,COX6A2, COX6B1, COX6B2, COX6C, COX7A1, COX7A2, COX7A2L, COX7B, COX7B2,COX7C, COX8A, COX8C, CP, CPA1, CPA2, CPA3, CPA4, CPA5, CPA6, CPAMD8,CPB1, CPB2, CPD, CPE, CPEB1, CPEB2, CPEB3, CPEB4, CPED1, CPLX1, CPLX2,CPLX3, CPLX4, CPM, CPN1, CPN2, CPNE1, CPNE2, CPNE3, CPNE4, CPNE5, CPNE6,CPNE7, CPNE8, CPNE9, CPO, CPOX, CPPED1, CPQ, CPS1, CPSF1, CPSF2, CPSF3,CPSF4, CPSF4L, CPSF6, CPSF7, CPT1A, CPT1B, CPT1C, CPT2, CPTP, CPVL,CPXCR1, CPXM1, CPXM2, CPZ, CR1, CR1L, CR2, CR354443.1, CR354443.2,CR388407.3, CR547123.3, CR753842.1, CR753845.2, CR759815.2, CR788250.1,CR847794.2, CR854858.1, CR933783.3, CR936239.1, CRABP1, CRABP2, CRACR2A,CRACR2B, CRADD, CRAMP1, CRAT, CRB1, CRB2, CRB3, CRBN, CRCP, CRCT1,CREB1, CREB3, CREB3L1, CREB3L2, CREB3L3, CREB3L4, CREB5, CREBBP, CREBL2,CREBRF, CREBZF, CREG1, CREG2, CRELDI, CRELD2, CREM, CRH, CRHBP, CRHR1,CRHR2, CRIM1, CRIP1, CRIP2, CRIP3, CRIPT, CRISP1, CRISP2, CRISP3,CRISPLD1, CRISPLD2, CRK, CRKL, CRLF1, CRLF2, CRLF3, CRLS1, CRMP1,CRNKL1, CRNN, CROCC, CROCC2, CROT, CRP, CRTAC1, CRTAM, CRTAP, CRTC1,CRTC2, CRTC3, CRX, CRY1, CRY2, CRYAA, CRYAB, CRYBA1, CRYBA2, CRYBA4,CRYBB1, CRYBB2, CRYBB3, CRYBG1, CRYBG2, CRYBG3, CRYGA, CRYGB, CRYGC,CRYGD, CRYGN, CRYGS, CRYL1, CRYM, CRYZ, CRYZL1, CS, CSAD, CSAG1, CSAG2,CSAG3, CSDC2, CSDE1, CSE1L, CSF1, CSF1R, CSF2, CSF2RA, CSF2RB, CSF3,CSF3R, CSGALNACT1, CSGALNACT2, CSH1, CSH2, CSHL1, CSK, CSMD1, CSMD2,CSMD3, CSN1S1, CSN2, CSN3, CSNK1A1, CSNK1A1L, CSNKlD, CSNK1E, CSNK1G1,CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CSNK2A3, CSNK2B, CSPG4, CSPG5,CSPP1, CSRNP1, CSRNP2, CSRNP3, CSRP1, CSRP2, CSRP3, CST1, CST11, CST2,CST3, CST4, CST5, CST6, CST7, CST8, CST9, CST9L, CSTA, CSTB, CSTF1,CSTF2, CSTF2T, CSTF3, CSTL1, CT45A1, CT45A10, CT45A2, CT45A3, CT45A5,CT45A6, CT45A7, CT45A8, CT45A9, CT476828.1, CT476828.10, CT476828.11,CT476828.12, CT476828.13, CT476828.14, CT476828.15, CT476828.16,CT476828.17, CT476828.18, CT476828.19, CT476828.2, CT476828.20,CT476828.21, CT476828.22, CT476828.3, CT476828.4, CT476828.5,CT476828.6, CT476828.7, CT476828.8, CT476828.9, CT47A1, CT47A10,CT47A11, CT47A12, CT47A2, CT47A3, CT47A4, CT47A5, CT47A6, CT47A7,CT47A8, CT47A9, CT47B1, CT55, CT62, CT83, CTAG1A, CTAG1B, CTAG2, CTAGEl,CTAGE15, CTAGE4, CTAGE5, CTAGE6, CTAGE8, CTAGE9, CTBP1, CTBP2, CTBS,CTC1, CTCF, CTCFL, CTDNEP1, CTDP1, CTDSP1, CTDSP2, CTDSPL, CTDSPL2,CTF1, CTGF, CTH, CTHRC1, CTIF, CTLA4, CTNNA1, CTNNA2, CTNNA3, CTNNAL1,CTNNB1, CTNNBIP1, CTNNBL1, CTNND1, CTNND2, CTNS, CTPS1, CTPS2, CTR9,CTRB1, CTRB2, CTRC, CTRL, CTSA, CTSB, CTSC, CTSD, CTSE, CTSF, CTSG,CTSH, CTSK, CTSL, CTSO, CTSS, CTSV, CTSW, CTSZ, CTTN, CTTNBP2,CTTNBP2NL, CTU1, CTU2, CTXN1, CTXN2, CTXN3, CTXND1, CU464060.1,CU633846.1, CU633980.1, CU633980.2, CU639417.1, CU639417.2, CUBN,CUEDC1, CUEDC2, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, CUL9, CUTA,CUTC, CUX1, CUX2, CUZD1, CWC15, CWC22, CWC25, CWC27, CWF19L1, CWF19L2,CWH43, CX3CL1, CX3CR1, CXADR, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13,CXCL14, CXCL16, CXCL17, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CXCL9, CXCR1,CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXorf21, CXorf36, CXorf38, CXorf40A,CXorf40B, CXorf49, CXorf49B, CXorf51A, CXorf51B, CXorf56, CXorf57,CXorf58, CXorf65, CXorf66, CXorf67, CXXC1, CXXC4, CXXC5, CYB561,CYB561A3, CYB561D1, CYB561D2, CYB5A, CYB5B, CYB5D1, CYB5D2, CYB5R1,CYB5R2, CYB5R3, CYB5R4, CYB5RL, CYBA, CYBB, CYBRD1, CYC1, CYCS, CYFIP1,CYFIP2, CYGB, CYHR1, CYLC1, CYLC2, CYLD, CYP11A1, CYP11B1, CYP11B2,CYP17A1, CYP19A1, CYP1A1, CYP1A2, CYP1B1, CYP20A1, CYP21A2, CYP24A1,CYP26A1, CYP26B1, CYP26C1, CYP27A1, CYP27B1, CYP27C1, CYP2A13, CYP2A6,CYP2A7, CYP2B6, CYP2C18, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2D7,CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1, CYP39A1, CYP3A4,CYP3A43, CYP3A5, CYP3A7, CYP3A7-CYP3A51P, CYP46A1, CYP4A11, CYP4A22,CYP4B1, CYP4F11, CYP4F12, CYP4F2, CYP4F22, CYP4F3, CYP4F8, CYP4V2,CYP4X1, CYP4Z1, CYP51A1, CYP7A1, CYP7B1, CYP8B1, CYR61, CYS1, CYSLTR1,CYSLTR2, CYSRT1, CYSTM1, CYTH1, CYTH2, CYTH3, CYTH4, CYTIP, CYTL1,CYYR1, D2HGDH, DAAM1, DAAM2, DAB1, DAB2, DAB2IP, DACH1, DACH2, DACT1,DACT2, DACT3, DAD1, DAG1, DAGLA, DAGLB, DALRD3, DAND5, DAO, DAOA, DAP,DAP3, DAPK1, DAPK2, DAPK3, DAPL1, DAPP1, DARS, DARS2, DAW1, DAXX, DAZ1,DAZ2, DAZ3, DAZ4, DAZAP1, DAZAP2, DAZL, DBF4, DBF4B, DBH, DBI, DBN1,DBNDD1, DBNDD2, DBNL, DBP, DBR1, DBT, DBX1, DBX2, DCAF1, DCAF10, DCAF11,DCAF12, DCAF12L1, DCAF12L2, DCAF13, DCAF15, DCAF16, DCAF17, DCAF4,DCAF4L1, DCAF4L2, DCAF5, DCAF6, DCAF7, DCAF8, DCAF8L1, DCAF8L2, DCAKD,DCANP1, DCBLD1, DCBLD2, DCC, DCD, DCDC1, DCDC2, DCDC2B, DCDC2C, DCHS1,DCHS2, DCK, DCLK1, DCLK2, DCLK3, DCLRElA, DCLRElB, DCLRElC, DCN, DCP1A,DCP1B, DCP2, DCPS, DCST1, DCST2, DCSTAMP, DCT, DCTD, DCTN1, DCTN2,DCTN3, DCTN4, DCTN5, DCTN6, DCTPP1, DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4,DCUN1D5, DCX, DCXR, DDA1, DDAH1, DDAH2, DDB1, DDB2, DDC, DDHD1, DDHD2,DDI1, DDI2, DDIAS, DDIT3, DDIT4, DDIT4L, DDN, DDO, DDOST, DDR1, DDR2,DDRGK1, DDT, DDTL, DDX1, DDX10, DDX11, DDX17, DDX18, DDX19A, DDX19B,DDX20, DDX21, DDX23, DDX24, DDX25, DDX27, DDX28, DDX31, DDX39A, DDX39B,DDX3X, DDX3Y, DDX4, DDX41, DDX42, DDX43, DDX46, DDX47, DDX49, DDX5,DDX50, DDX51, DDX52, DDX53, DDX54, DDX55, DDX56, DDX58, DDX59, DDX6,DDX60, DDX60L, DEAF1, DEC 1, DECR1, DECR2, DEDD, DEDD2, DEF6, DEF8,DEFA1, DEFAIB, DEFA3, DEFA4, DEFA5, DEFA6, DEFB1, DEFB103A, DEFB103B,DEFB104A, DEFB104B, DEFB105A, DEFB105B, DEFB106A, DEFB106B, DEFB107A,DEFB107B, DEFB108B, DEFB110, DEFB112, DEFB113, DEFB114, DEFB115,DEFB116, DEFB118, DEFB119, DEFB121, DEFB123, DEFB124, DEFB125, DEFB126,DEFB127, DEFB128, DEFB129, DEFB130A, DEFB130B, DEFB131A, DEFB131B,DEFB132, DEFB133, DEFB134, DEFB135, DEFB136, DEFB4A, DEFB4B, DEGS1,DEGS2, DEK, DENND1A, DENND1B, DENNDl1C, DENND2A, DENND2C, DENND2D,DENND3, DENND4A, DENND4B, DENND4C, DENND5A, DENND5B, DENND6A, DENND6B,DENR, DEPDC1, DEPDClB, DEPDC4, DEPDC5, DEPDC7, DEPTOR, DERA, DERL1,DERL2, DERL3, DES, DESI1, DESI2, DET1, DEUP1, DEXI, DFFA, DFFB, DFNA5,DFNB59, DGAT1, DGAT2, DGAT2L6, DGCR2, DGCR6, DGCR6L, DGCR8, DGKA, DGKB,DGKD, DGKE, DGKG, DGKH, DGKI, DGKK, DGKQ, DGKZ, DGUOK, DHCR24, DHCR7,DHDDS, DHDH, DHFR, DHFR2, DHH, DHODH, DHPS, DHRS1, DHRS11, DHRS12,DHRS13, DHRS2, DHRS3, DHRS4, DHRS4L2, DHRS7, DHRS7B, DHRS7C, DHRS9,DHRSX, DHTKD1, DHX15, DHX16, DHX29, DHX30, DHX32, DHX33, DHX34, DHX35,DHX36, DHX37, DHX38, DHX40, DHX57, DHX58, DHX8, DHX9, DIABLO, DIAPHI,DIAPH2, DIAPH3, DICERI, DIDO1, DIEXF, DIMT1, DIO1, DI02, DI03, DIP2A,DIP2B, DIP2C, DIRAS1, DIRAS2, DIRAS3, DIRC1, DIRC2, DIRC3, DIS3, DIS3L,DIS3L2, DISCI, DISP1, DISP2, DISP3, DIXDC1, DKC1, DKK1, DKK2, DKK3,DKK4, DKKL1, DLAT, DLC1, DLD, DLEC1, DLEU7, DLG1, DLG2, DLG3, DLG4,DLG5, DLGAP1, DLGAP2, DLGAP3, DLGAP4, DLGAP5, DLK1, DLK2, DLL1, DLL3,DLL4, DLST, DLX1, DLX2, DLX3, DLX4, DLX5, DLX6, DMAC1, DMAC2, DMAP1,DMBT1, DMBX1, DMC1, DMD, DMGDH, DMKN, DMP1, DMPK, DMRT1, DMRT2, DMRT3,DMRTA1, DMRTA2, DMRTB1, DMRTC1, DMRTC1B, DMRTC2, DMTF1, DMTN, DMWD,DMXL1, DMXL2, DNA2, DNAAF1, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAH1,DNAH10, DNAH10OS, DNAH11, DNAH12, DNAH14, DNAH17, DNAH2, DNAH3, DNAH5,DNAH6, DNAH7, DNAH8, DNAH9, DNAI1, DNAI2, DNAJA1, DNAJA2, DNAJA3,DNAJA4, DNAJB1, DNAJB11, DNAJB12, DNAJB13, DNAJB14, DNAJB2, DNAJB4,DNAJB5, DNAJB6, DNAJB7, DNAJB8, DNAJB9, DNAJC1, DNAJC10, DNAJC11,DNAJC12, DNAJC13, DNAJC14, DNAJC15, DNAJC16, DNAJC17, DNAJC18, DNAJC19,DNAJC2, DNAJC21, DNAJC22, DNAJC24, DNAJC25, DNAJC25-GNG10, DNAJC27,DNAJC28, DNAJC3, DNAJC30, DNAJC4, DNAJC5, DNAJC5B, DNAJC5G, DNAJC6,DNAJC7, DNAJC8, DNAJC9, DNAL1, DNAL4, DNALIl, DNASEl, DNASE1L1,DNASE1L2, DNASE1L3, DNASE2, DNASE2B, DND1, DNER, DNHD1, DNLZ, DNM1,DNM1L, DNM2, DNM3, DNMBP, DNMT1, DNMT3A, DNMT3B, DNMT3L, DNPEP, DNPH1,DNTT, DNTTIP1, DNTTIP2, DOC2A, DOC2B, DOCK1, DOCK10, DOCK11, DOCK2,DOCK3, DOCK4, DOCK5, DOCK6, DOCK7, DOCK8, DOCK9, DOHH, DOK1, DOK2, DOK3,DOK4, DOK5, DOK6, DOK7, DOLK, DOLPP1, DONSON, DOPEY1, DOPEY2, DOT1L,DPAGT1, DPCD, DPCR1, DPEP1, DPEP2, DPEP3, DPF1, DPF2, DPF3, DPH1, DPH2,DPH3, DPH5, DPH6, DPH7, DPM1, DPM2, DPM3, DPP10, DPP3, DPP4, DPP6, DPP7,DPP8, DPP9, DPPA2, DPPA3, DPPA4, DPPA5, DPRX, DPT, DPY19L1, DPY19L2,DPY19L3, DPY19L4, DPY30, DPYD, DPYS, DPYSL2, DPYSL3, DPYSL4, DPYSL5,DQX1, DR1, DRAM1, DRAM2, DRAP1, DRAXIN, DRC1, DRC3, DRC7, DRD1, DRD2,DRD3, DRD4, DRD5, DRG1, DRG2, DRGX, DRICHI, DROSHA, DRP2, DSC1, DSC2,DSC3, DSCAM, DSCAML1, DSCC1, DSCR3, DSCR4, DSCR8, DSE, DSEL, DSG1, DSG2,DSG3, DSG4, DSN1, DSP, DSPP, DST, DSTN, DSTYK, DTD1, DTD2, DTHD1, DTL,DTNA, DTNB, DTNBP1, DTWD1, DTWD2, DTX1, DTX2, DTX3, DTX3L, DTX4, DTYMK,DUOX1, DUOX2, DUOXA1, DUOXA2, DUPD1, DUS1L, DUS2, DUS3L, DUS4L, DUSP1,DUSP10, DUSP11, DUSP12, DUSP13, DUSP14, DUSP15, DUSP16, DUSP18, DUSP19,DUSP2, DUSP21, DUSP22, DUSP23, DUSP26, DUSP27, DUSP28, DUSP3, DUSP4,DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, DUT, DUX4, DUXA, DUXB, DVL1, DVL2,DVL3, DWORF, DXO, DYDC1, DYDC2, DYM, DYNAP, DYNC1H1, DYNC1I1, DYNC1I2,DYNC1LI1, DYNC1LI2, DYNC2H1, DYNC2LI1, DYNLL1, DYNLL2, DYNLRB1, DYNLRB2,DYNLT1, DYNLT3, DYRKIA, DYRKIB, DYRK2, DYRK3, DYRK4, DYSF, DYTN, DZANK1,DZIP1, DZIP1L, DZIP3, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8,E4F1, EAF1, EAF2, EAPP, EARS2, EBAG9, EBF1, EBF2, EBF3, EBF4, EBI3,EBLN1, EBLN2, EBNA1BP2, EBP, EBPL, ECD, ECE1, ECE2, ECEL1, ECH1, ECHDC1,ECHDC2, ECHDC3, ECHS1, ECIl, ECI2, ECM1, ECM2, ECSCR, ECSIT, ECT2,ECT2L, EDA, EDA2R, EDAR, EDARADD, EDC3, EDC4, EDDM13, EDDM3A, EDDM3B,EDEM1, EDEM2, EDEM3, EDF1, EDIL3, EDN1, EDN2, EDN3, EDNRA, EDNRB, EDRF1,EEA1, EED, EEF1A1, EEF1A2, EEF1AKMT1, EEF1AKMT2, EEF1AKMT3, EEF1B2,EEF1D, EEF1E1, EEF1E1-BLOC1S5, EEF1G, EEF2, EEF2K, EEF2KMT, EEFSEC,EEPD1, EFCAB1, EFCAB10, EFCAB11, EFCAB12, EFCAB13, EFCAB14, EFCAB2,EFCAB3, EFCAB5, EFCAB6, EFCAB7, EFCAB8, EFCAB9, EFCC1, EFEMPI, EFEMP2,EFHB, EFHC1, EFHC2, EFHD1, EFHD2, EFL1, EFNA1, EFNA2, EFNA3, EFNA4,EFNA5, EFNB1, EFNB2, EFNB3, EFR3A, EFR3B, EFS, EFTUD2, EGF, EGFL6,EGFL7, EGFL8, EGFLAM, EGFR, EGLN1, EGLN2, EGLN3, EGR1, EGR2, EGR3, EGR4,EHBP1, EHBP1L1, EHD1, EHD2, EHD3, EHD4, EHF, EHHADH, EHMT1, EHMT2, E124,EID1, EID2, EID2B, EID3, EIF1, EIF1AD, EIF1AX, EIF1AY, EIF1B, EIF2A,EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4, EIF2B1, EIF2B2, EIF2B3, EIF2B4,EIF2B5, EIF2D, EIF2S1, EIF2S2, EIF2S3, EIF3A, EIF3B, EIF3C, EIF3CL,EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L, EIF3M,EIF4A1, EIF4A2, EIF4A3, EIF4B, EIF4E, EIF4E1B, EIF4E2, EIF4E3, EIF4EBP1,EIF4EBP2, EIF4EBP3, EIF4ENIF1, EIF4G1, EIF4G2, EIF4G3, EIF4H, EIF5,EIF5A, EIF5A2, EIF5AL1, EIF5B, EIF6, EIPR1, ELAC1, ELAC2, ELANE, ELAVL1,ELAVL2, ELAVL3, ELAVL4, ELF1, ELF2, ELF3, ELF4, ELF5, ELFN1, ELFN2,ELK1, ELK3, ELK4, ELL, ELL2, ELL3, ELMO1, ELMO2, ELMO3, ELMOD1, ELMOD2,ELMOD3, ELMSAN1, ELN, ELOA, ELOA2, ELOA3, ELOA3B, ELOA3C, ELOA3D, ELOB,ELOC, ELOF1, ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, ELOVL7,ELP1, ELP2, ELP3, ELP4, ELP5, ELP6, ELSPBP1, EMB, EMC1, EMC10, EMC2,EMC3, EMC4, EMC6, EMC7, EMC8, EMC9, EMCN, EMD, EME1, EME2, EMG1, EMID1,EMILIN1, EMILIN2, EMILIN3, EML1, EML2, EML3, EML4, EML5, EML6, EMP1,EMP2, EMP3, EMSY, EMX1, EMX2, EN1, EN2, ENAH, ENAM, ENC1, ENDOD1, ENDOG,ENDOU, ENDOV, ENG, ENGASE, ENHO, ENKD1, ENKUR, ENO1, ENO2, ENO3, ENO4,ENOPH1, ENOSF1, ENOX1, ENOX2, ENPEP, ENPP1, ENPP2, ENPP3, ENPP4, ENPP5,ENPP6, ENPP7, ENSA, ENTHDI, ENTPD1, ENTPD2, ENTPD3, ENTPD4, ENTPD5,ENTPD6, ENTPD7, ENTPD8, ENY2, EOGT, EOMES, EP300, EP400, EPAS1, EPB41,EPB41L1, EPB41L2, EPB41L3, EPB41L4A, EPB41L4B, EPB41L5, EPB42, EPC1,EPC2, EPCAM, EPDR1, EPG5, EPGN, EPHA1, EPHA10, EPHA2, EPHA3, EPHA4,EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, EPHX1,EPHX2, EPHX3, EPHX4, EPM2A, EPM2AIP1, EPN1, EPN2, EPN3, EPO, EPOP, EPOR,EPPIN, EPPIN-WFDC6, EPPK1, EPRS, EPS15, EPS15L1, EPS8, EPS8L1, EPS8L2,EPS8L3, EPSTIl, EPX, EPYC, EQTN, ERAL1, ERAP1, ERAP2, ERAS, ERBB2,ERBB3, ERBB4, ERBIN, ERC1, ERC2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5,ERCC6, ERCC6L, ERCC6L2, ERCC8, EREG, ERF, ERFE, ERG, ERG28, ERGICI,ERGIC2, ERGIC3, ERH, ERI1, ERI2, ERI3, ERICH1, ERICH2, ERICH3, ERICH4,ERICH5, ERICH6, ERICH6B, ERLEC1, ERLIN1, ERLIN2, ERMAP, ERMARD, ERMN,ERMP1, ERN1, ERN2, ERO1A, ERO1B, ERP27, ERP29, ERP44, ERRFI1, ERV3-1,ERVFRD-1, ERVMER34-1, ERVV-1, ERVV-2, ERVW-1, ESAM, ESCO1, ESCO2, ESD,ESF1, ESM1, ESPL1, ESPN, ESPNL, ESR1, ESR2, ESRP1, ESRP2, ESRRA, ESRRB,ESRRG, ESS2, ESX1, ESYT1, ESYT2, ESYT3, ETAA1, ETDA, ETDB, ETDC, ETF1,ETFA, ETFB, ETFBKMT, ETFDH, ETFRF1, ETHEl, ETNK1, ETNK2, ETNPPL, ETS1,ETS2, ETV1, ETV2, ETV3, ETV3L, ETV4, ETV5, ETV6, ETV7, EVA1A, EVA1B,EVA1C, EVC, EVC2, EVI2A, EVI2B, EVI5, EVI5L, EVL, EVPL, EVPLL, EVX1,EVX2, EWSR1, EXD1, EXD2, EXD3, EXO1, EX05, EXOC1, EXOCIL, EXOC2, EXOC3,EXOC3L1, EXOC3L2, EXOC3L4, EXOC4, EXOC5, EXOC6, EXOC6B, EXOC7, EXOC8,EXOG, EXOSCI, EXOSC10, EXOSC2, EXOSC3, EXOSC4, EXOSC5, EXOSC6, EXOSC7,EXOSC8, EXOSC9, EXPH5, EXT1, EXT2, EXTL1, EXTL2, EXTL3, EYA1, EYA2,EYA3, EYA4, EYS, EZH1, EZH2, EZR, F10, F11, F11R, F12, F13A1, F13B, F2,F2R, F2RL1, F2RL2, F2RL3, F3, F5, F7, F8, F8A1, F8A2, F8A3, F9, FA2H,FAAH, FAAH2, FAAP100, FAAP20, FAAP24, FABP1, FABP12, FABP2, FABP3,FABP4, FABP5, FABP6, FABP7, FABP9, FADD, FADS1, FADS2, FADS3, FADS6,FAF1, FAF2, FAH, FAHD1, FAHD2A, FAHD2B, FAIM, FAIM2, FAM102A, FAM102B,FAM103A1, FAM104A, FAM104B, FAM105A, FAM106A, FAM107A, FAM107B, FAM109A,FAM109B, FAM110A, FAM110B, FAM110C, FAM110D, FAM111A, FAM111B, FAM114A1,FAM114A2, FAM117A, FAM117B, FAM118A, FAM118B, FAM120A, FAM120AOS,FAM120B, FAM120C, FAM122A, FAM122B, FAM122C, FAM124A, FAM124B, FAM126A,FAM126B, FAM129A, FAM129B, FAM129C, FAM131A, FAM131B, FAM131C, FAM133A,FAM133B, FAM135A, FAM135B, FAM136A, FAM13A, FAM13B, FAM13C, FAM149A,FAM149B1, FAM151A, FAM151B, FAM153A, FAM153B, FAM153C, FAM155A, FAM155B,FAM156A, FAM156B, FAM159A, FAM159B, FAM160A1, FAM160A2, FAM160B1,FAM160B2, FAM161A, FAM161B, FAM162A, FAM162B, FAM163A, FAM163B, FAM166A,FAM166B, FAM167A, FAM167B, FAM168A, FAM168B, FAM169A, FAM169B, FAM170A,FAM170B, FAM171A1, FAM171A2, FAM171B, FAM172A, FAM173A, FAM173B,FAM174A, FAM174B, FAM177A1, FAM177B, FAM178B, FAM180A, FAM180B, FAM181A,FAM181B, FAM182B, FAM183A, FAM184A, FAM184B, FAM185A, FAM186A, FAM186B,FAM187A, FAM187B, FAM189A1, FAM189A2, FAM189B, FAM192A, FAM193A,FAM193B, FAM196A, FAM196B, FAM198A, FAM198B, FAM199X, FAM19A1, FAM19A2,FAM19A3, FAM19A4, FAM19A5, FAM200A, FAM200B, FAM204A, FAM205A, FAM205C,FAM206A, FAM207A, FAM208A, FAM208B, FAM209A, FAM209B, FAM20A, FAM20B,FAM20C, FAM210A, FAM210B, FAM212A, FAM212B, FAM213A, FAM213B, FAM214A,FAM214B, FAM216A, FAM216B, FAM217A, FAM217B, FAM218A, FAM219A, FAM219B,FAM220A, FAM221A, FAM221B, FAM222A, FAM222B, FAM227A, FAM227B, FAM228A,FAM228B, FAM229A, FAM229B, FAM230A, FAM231A, FAM231B, FAM231C, FAM231D,FAM234A, FAM234B, FAM236A, FAM236B, FAM236C, FAM236D, FAM237A, FAM237B,FAM240A, FAM240B, FAM24A, FAM24B, FAM25A, FAM25C, FAM25G, FAM26D,FAM26E, FAM26F, FAM32A, FAM35A, FAM3A, FAM3B, FAM3C, FAM3D, FAM43A,FAM43B, FAM45A, FAM46A, FAM46B, FAM46C, FAM46D, FAM47A, FAM47B, FAM47C,FAM47E, FAM47E-STBD1, FAM49A, FAM49B, FAM50A, FAM50B, FAM53A, FAM53B,FAM53C, FAM57A, FAM57B, FAM58A, FAM60A, FAM69A, FAM69B, FAM69C, FAM71A,FAM71B, FAM71C, FAM71D, FAM71E1, FAM71E2, FAM71F1, FAM71F2, FAM72A,FAM72B, FAM72C, FAM72D, FAM76A, FAM76B, FAM78A, FAM78B, FAM81A, FAM81B,FAM83A, FAM83B, FAM83C, FAM83D, FAM83E, FAM83F, FAM83G, FAM83H, FAM84A,FAM84B, FAM86B1, FAM86B2, FAM86C1, FAM89A, FAM89B, FAM8A1, FAM90A1,FAM90A26, FAM91A1, FAM92A, FAM92B, FAM95C, FAM96A, FAM96B, FAM98A,FAM98B, FAM98C, FAM9A, FAM9B, FAM9C, FAN1, FANCA, FANCB, FANCC, FANCD2,FANCD2OS, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANK1, FAP, FAR1,FAR2, FARP1, FARP2, FARS2, FARSA, FARSB, FAS, FASLG, FASN, FASTK,FASTKD1, FASTKD2, FASTKD3, FASTKD5, FAT1, FAT2, FAT3, FAT4, FATE1, FAU,FAXC, FAXDC2, FBF1, FBL, FBLIM1, FBLL1, FBLN1, FBLN2, FBLN5, FBLN7,FBN1, FBN2, FBN3, FBP1, FBP2, FBRS, FBRSL1, FBXL12, FBXL13, FBXL14,FBXL15, FBXL16, FBXL17, FBXL18, FBXL19, FBXL2, FBXL20, FBXL22, FBXL3,FBXL4, FBXL5, FBXL6, FBXL7, FBXL8, FBXO10, FBXO11, FBX015, FBX016,FBX017, FBX018, FBXO2, FBXO21, FBXO22, FBXO24, FBXO25, FBXO27, FBXO28,FBXO3, FBXO30, FBXO31, FBXO32, FBXO33, FBXO34, FBXO36, FBXO38, FBXO39,FBXO4, FBXO40, FBXO41, FBXO42, FBXO43, FBXO44, FBXO45, FBXO46, FBXO47,FBXO48, FBX05, FBXO6, FBXO7, FBXO8, FBXO9, FBXW10, FBXW11, FBXW12,FBXW2, FBXW4, FBXW5, FBXW7, FBXW8, FBXW9, FCAMR, FCAR, FCER1A, FCER1G,FCER2, FCF1, FCGBP, FCGR1A, FCGR1B, FCGR2A, FCGR2B, FCGR2C, FCGR3A,FCGR3B, FCGRT, FCHO1, FCHO2, FCHSD1, FCHSD2, FCMR, FCN1, FCN2, FCN3,FCRL1, FCRL2, FCRL3, FCRL4, FCRL5, FCRL6, FCRLA, FCRLB, FDCSP, FDFT1,FDPS, FDX1, FDX2, FDXACB1, FDXR, FECH, FEM1A, FEM1B, FEM1C, FEN1, FER,FER1L5, FER1L6, FERD3L, FERMT1, FERMT2, FERMT3, FES, FETUB, FEV, FEZ1,FEZ2, FEZF1, FEZF2, FFAR1, FFAR2, FFAR3, FFAR4, FGA, FGB, FGD1, FGD2,FGD3, FGD4, FGD5, FGD6, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16,FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5,FGF6, FGF7, FGF8, FGF9, FGFBP1, FGFBP2, FGFBP3, FGFR1, FGFR1OP,FGFR1OP2, FGFR2, FGFR3, FGFR4, FGFRL1, FGG, FGGY, FGL1, FGL2, FGR, FH,FHAD1, FHDC1, FHIT, FHL1, FHL2, FHL3, FHL5, FHOD1, FHOD3, FIBCD1, FIBIN,FIBP, FICD, FIG4, FIGLA, FIGN, FIGNL1, FIGNL2, FILTP1, FILIP1L, FIP1L1,FIS1, FITM1, FITM2, FIZ1, FJX1, FKBP10, FKBP11, FKBP14, FKBP15, FKBPlA,FKBP1B, FKBP1C, FKBP2, FKBP3, FKBP4, FKBP5, FKBP6, FKBP7, FKBP8, FKBP9,FKBPL, FKRP, FKTN, FLAD1, FLCN, FLG, FLG2, FLI1, FLII, FLNA, FLNB, FLNC,FLOT1, FLOT2, FLRT1, FLRT2, FLRT3, FLT1, FLT3, FLT3LG, FLT4, FLVCR1,FLVCR2, FLYWCH1, FLYWCH2, FMC1, FMN1, FMN2, FMNL1, FMNL2, FMNL3, FMO1,FMO2, FMO3, FMO4, FMO5, FMOD, FMR1, FMR1NB, FN1, FN3K, FN3KRP, FNBP1,FNBP1L, FNBP4, FNDC1, FNDC10, FNDC11, FNDC3A, FNDC3B, FNDC4, FNDC5,FNDC7, FNDC8, FNDC9, FNIP1, FNIP2, FNTA, FNTB, F0681492.1, F0681542.1,FOCAD, FOLH1, FOLR1, FOLR2, FOLR3, FOPNL, FOS, FOSB, FOSL1, FOSL2,FOXA1, FOXA2, FOXA3, FOXB1, FOXB2, FOXC1, FOXC2, FOXD1, FOXD2, FOXD3,FOXD4, FOXD4L1, FOXD4L3, FOXD4L4, FOXD4L5, FOXD4L6, FOXE1, FOXE3, FOXF1,FOXF2, FOXG1, FOXH1, FOXI1, FOXI2, FOXI3, FOXJ1, FOXJ2, FOXJ3, FOXK1,FOXK2, FOXL1, FOXL2, FOXL2NB, FOXM1, FOXN1, FOXN2, FOXN3, FOXN4, FOXO1,FOXO3, FOXO4, FOXO6, FOXP1, FOXP2, FOXP3, FOXP4, FOXQ1, FOXR1, FOXR2,FOXRED1, FOXRED2, FOXS1, FP236240.1, FP565260.1, FP565260.2, FP565260.3,FP565260.4, FP565260.6, FP565260.7, FP565324.1, FP565324.2, FPGS, FPGT,FPGT-TNNI3K, FPR1, FPR2, FPR3, FRA1OAC1, FRAS1, FRAT1, FRAT2, FREM1,FREM2, FREM3, FRG1, FRG2, FRG2B, FRG2C, FRK, FRMD1, FRMD3, FRMD4A,FRMD4B, FRMD5, FRMD6, FRMD7, FRMD8, FRMPD1, FRMPD2, FRMPD3, FRMPD4,FRRS1, FRRS1L, FRS2, FRS3, FRY, FRYL, FRZB, FSBP, FSCB, FSCN1, FSCN2,FSCN3, FSD1, FSD1L, FSD2, FSHB, FSHR, FSIP1, FSIP2, FST, FSTL1, FSTL3,FSTL4, FSTL5, FTCD, FTCDNL1, FTH1, FTHL17, FTL, FTMT, FTO, FTSJ1, FTSJ3,FUBP1, FUBP3, FUCA1, FUCA2, FUK, FUNDC1, FUNDC2, FUOM, FURIN, FUS, FUT1,FUT10, FUT11, FUT2, FUT3, FUT4, FUT5, FUT6, FUT7, FUT8, FUT9, FUZ, FXN,FXR1, FXR2, FXYD1, FXYD2, FXYD3, FXYD4, FXYD5, FXYD6, FXYD6-FXYD2,FXYD7, FYB1, FYB2, FYCO1, FYN, FYTTD1, FZD1, FZD10, FZD2, FZD3, FZD4,FZD5, FZD6, FZD7, FZD8, FZD9, FZR1, GOS2, G2E3, G3BP1, G3BP2, G6PC,G6PC2, G6PC3, G6PD, GAA, GAB1, GAB2, GAB3, GAB4, GABARAP, GABARAPLI,GABARAPL2, GABBR1, GABBR2, GABPA, GABPB1, GABPB2, GABRA1, GABRA2,GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRB3, GABRD, GABRE,GABRG1, GABRG2, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, GAD1,GAD2, GADD45A, GADD45B, GADD45G, GADD45GIP1, GADL1, GAGE1, GAGE10,GAGE12B, GAGE12C, GAGE12D, GAGE12E, GAGE12F, GAGE12G, GAGE12H, GAGE12J,GAGE13, GAGE2A, GAGE2E, GAK, GAL, GAL3ST1, GAL3ST2, GAL3ST3, GAL3ST4,GALC, GALE, GALK1, GALK2, GALM, GALNS, GALNT1, GALNT10, GALNT11,GALNT12, GALNT13, GALNT14, GALNT15, GALNT16, GALNT17, GALNT18, GALNT2,GALNT3, GALNT4, GALNT5, GALNT6, GALNT7, GALNT8, GALNT9, GALNTL5,GALNTL6, GALP, GALR1, GALR2, GALR3, GALT, GAMT, GAN, GANAB, GANC, GAP43,GAPDH, GAPDHS, GAPT, GAPVD1, GAR1, GAREMI, GAREM2, GARNL3, GARS, GART,GAS1, GAS2, GAS2L1, GAS2L2, GAS2L3, GAS6, GAS7, GAS8, GAST, GATA1,GATA2, GATA3, GATA4, GATA5, GATA6, GATADI, GATAD2A, GATAD2B, GATB, GATC,GATD1, GATM, GATS, GBA, GBA2, GBA3, GBE1, GBF1, GBGT1, GBP1, GBP2, GBP3,GBP4, GBP5, GBP6, GBP7, GBX1, GBX2, GC, GCA, GCAT, GCC1, GCC2, GCDH,GCFC2, GCG, GCGR, GCH1, GCHFR, GCK, GCKR, GCLC, GCLM, GCM1, GCM2, GCN1,GCNA, GCNT1, GCNT2, GCNT3, GCNT4, GCNT7, GCOM1, GCSAM, GCSAML, GCSH,GDA, GDAP1, GDAP1L1, GDAP2, GDE1, GDF1, GDF10, GDF11, GDF15, GDF2, GDF3,GDF5, GDF5OS, GDF6, GDF7, GDF9, GDI1, GDI2, GDNF, GDPD1, GDPD2, GDPD3,GDPD4, GDPD5, GDPGP1, GEM, GEMIN2, GEMIN4, GEMIN5, GEMIN6, GEMIN7,GEMIN8, GEN1, GET4, GFAP, GFER, GFI1, GFI1B, GFM1, GFM2, GFOD1, GFOD2,GFPT1, GFPT2, GFRA1, GFRA2, GFRA3, GFRA4, GFRAL, GFY, GGA1, GGA2, GGA3,GGACT, GGCT, GGCX, GGH, GGN, GGNBP2, GGPS1, GGT1, GGT2, GGT5, GGT6,GGT7, GGTLC1, GGTLC2, GGTLC3, GH1, GH2, GHDC, GHITM, GHR, GHRH, GHRHR,GHRL, GHSR, GID4, GID8, GIF, GIGYF1, GIGYF2, GIMAP1, GIMAP1-GIMAP5,GIMAP2, GIMAP4, GIMAP5, GIMAP6, GIMAP7, GIMAP8, GIMDI1, GIN1, GINM1,GINS1, GINS2, GINS3, GINS4, GIP, GIPC1, GIPC2, GIPC3, GIPR, GIT1, GIT2,GJA1, GJA10, GJA3, GJA4, GJA5, GJA8, GJA9, GJB1, GJB2, GJB3, GJB4, GJB5,GJB6, GJB7, GJC1, GJC2, GJC3, GJD2, GJD3, GJD4, GJE1, GK, GK2, GK3P,GK5, GKAP1, GKN1, GKN2, GLA, GLB1, GLB1L, GLB1L2, GLB1L3, GLCCIl, GLCE,GLDC, GLDN, GLE1, GLG1, GLIl, GLI2, GLI3, GLI4, GLIPR1, GLIPR1L1,GLIPR1L2, GLIPR2, GLIS1, GLIS2, GLIS3, GLMN, GLMP, GLO1, GLOD4, GLOD5,GLP1R, GLP2R, GLRA1, GLRA2, GLRA3, GLRA4, GLRB, GLRX, GLRX2, GLRX3,GLRX5, GLS, GLS2, GLT1D1, GLT6D1, GLT8D1, GLT8D2, GLTP, GLTPD2, GLUD1,GLUD2, GLUL, GLYAT, GLYATL1, GLYATL1P3, GLYATL2, GLYATL3, GLYCTK, GLYR1,GM2A, GMCL1, GMDS, GMEB1, GMEB2, GMFB, GMFG, GMIP, GML, GMNC, GMNN,GMPPA, GMPPB, GMPR, GMPR2, GMPS, GNA11, GNA12, GNA13, GNA14, GNA15,GNAI1, GNAI2, GNAI3, GNAL, GNAO1, GNAQ, GNAS, GNAT1, GNAT2, GNAT3, GNAZ,GNB1, GNB1L, GNB2, GNB3, GNB4, GNB5, GNE, GNG10, GNG11, GNG12, GNG13,GNG14, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GNL1, GNL2,GNL3, GNL3L, GNLY, GNMT, GNPAT, GNPDA1, GNPDA2, GNPNAT1, GNPTAB, GNPTG,GNRH1, GNRH2, GNRHR, GNS, GOLGA1, GOLGA2, GOLGA3, GOLGA4, GOLGA5,GOLGA6A, GOLGA6B, GOLGA6C, GOLGA6D, GOLGA6L1, GOLGA6L10, GOLGA6L2,GOLGA6L22, GOLGA6L4, GOLGA6L6, GOLGA6L7P, GOLGA6L9, GOLGA7, GOLGA7B,GOLGA8A, GOLGA8B, GOLGA8F, GOLGA8G, GOLGA8H, GOLGA8J, GOLGA8K, GOLGA8M,GOLGA8N, GOLGA80, GOLGA8Q, GOLGA8R, GOLGA8S, GOLGA8T, GOLGB1, GOLIM4,GOLM1, GOLPH3, GOLPH3L, GOLTIA, GOLTIB, GON4L, GON7, GOPC, GORAB,GORASPI, GORASP2, GOSR1, GOSR2, GOT1, GOT1L1, GOT2, GP1BA, GP1BB, GP2,GP5, GP6, GP9, GPA33, GPAA1, GPALPP1, GPAM, GPANK1, GPAT2, GPAT3, GPAT4,GPATCH1, GPATCH11, GPATCH2, GPATCH2L, GPATCH3, GPATCH4, GPATCH8, GPBAR1,GPBP1, GPBP1L1, GPC1, GPC2, GPC3, GPC4, GPC5, GPC6, GPCPD1, GPD1, GPD1L,GPD2, GPER1, GPHA2, GPHB5, GPHN, GPI, GPIBP1, GPKOW, GPLD1, GPM6A,GPM6B, GPN1, GPN2, GPN3, GPNMB, GPR1, GPR101, GPR107, GPR108, GPR119,GPR12, GPR132, GPR135, GPR137, GPR137B, GPR137C, GPR139, GPR141, GPR142,GPR143, GPR146, GPR148, GPR149, GPR15, GPR150, GPR151, GPR152, GPR153,GPR155, GPR156, GPR157, GPR158, GPR160, GPR161, GPR162, GPR17, GPR171,GPR173, GPR174, GPR176, GPR179, GPR18, GPR180, GPR182, GPR183, GPR19,GPR20, GPR21, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, GPR32, GPR33,GPR34, GPR35, GPR37, GPR37L1, GPR39, GPR4, GPR42, GPR45, GPR50, GPR52,GPR55, GPR6, GPR61, GPR62, GPR63, GPR65, GPR68, GPR75, GPR75-ASB3,GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPR88, GPR89A, GPR89B,GPRASP1, GPRASP2, GPRC5A, GPRC5B, GPRC5C, GPRC5D, GPRC6A, GPRIN1,GPRIN2, GPRIN3, GPS1, GPS2, GPSM1, GPSM2, GPSM3, GPT, GPT2, GPX1, GPX2,GPX3, GPX4, GPX5, GPX6, GPX7, GPX8, GRAMD1A, GRAMD1B, GRAMD1C, GRAMD2A,GRAMD2B, GRAMD4, GRAP, GRAP2, GRAPL, GRASP, GRB10, GRB14, GRB2, GRB7,GREB1, GREB1L, GREM1, GREM2, GRHL1, GRHL2, GRHL3, GRHPR, GRIAl, GRIA2,GRIA3, GRIA4, GRID1, GRID2, GRID2IP, GRIFIN, GRIK1, GRIK2, GRIK3, GRIK4,GRIK5, GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRINA,GRIP1, GRIP2, GRIPAP1, GRK1, GRK2, GRK3, GRK4, GRK5, GRK6, GRK7, GRM1,GRM2, GRM3, GRM4, GRM5, GRM6, GRM7, GRM8, GRN, GRP, GRPEL1, GRPEL2,GRPR, GRSF1, GRTP1, GRWD1, GRXCR1, GRXCR2, GSAP, GSC, GSC2, GSDMA,GSDMB, GSDMC, GSDMD, GSE1, GSG1, GSG1L, GSG1L2, GSK3A, GSK3B, GSKIP,GSN, GSPT1, GSPT2, GSR, GSS, GSTA1, GSTA2, GSTA3, GSTA4, GSTA5, GSTCD,GSTK1, GSTM1, GSTM2, GSTM3, GSTM4, GSTM5, GSTO1, GSTO2, GSTP1, GSTT1,GSTT2, GSTT2B, GSTTP1, GSTZ1, GSX1, GSX2, GTDC1, GTF2A1, GTF2A1L,GTF2A2, GTF2B, GTF2E1, GTF2E2, GTF2F1, GTF2F2, GTF2H1, GTF2H2, GTF2H2C,GTF2H2C_2, GTF2H3, GTF2H4, GTF2H5, GTF2I, GTF2IRD1, GTF2IRD2, GTF2IRD2B,GTF3A, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5, GTF3C6, GTPBP1, GTPBP1O,GTPBP2, GTPBP3, GTPBP4, GTPBP6, GTPBP8, GTSE1, GTSF1, GTSF1L,GU182339.1, GU182339.3, GU182343.1, GU182343.2, GU182345.1, GU182345.2,GU182347.1, GU182351.2, GU182352.2, GU182353.1, GU182355.1, GU182355.2,GU182355.3, GU182357.1, GU182357.3, GU182359.1, GU182359.2, GUCA1A,GUCAIB, GUCAIC, GUCA2A, GUCA2B, GUCD1, GUCYlA2, GUCYlA3, GUCYlB3,GUCY2C, GUCY2D, GUCY2F, GUF1, GUK1, GULP1, GUSB, GVQW2, GXYLT1, GXYLT2,GYG1, GYG2, GYPA, GYPB, GYPC, GYPE, GYS1, GYS2, GZF1, GZMA, GZMB, GZMH,GZMK, GZMM, H1FO, H1FNT, H1FOO, H1FX, H2AFB1, H2AFB2, H2AFB3, H2AFJ,H2AFV, H2AFX, H2AFY, H2AFY2, H2AFZ, H2BFM, H2BFS, H2BFWT, H3F3A, H3F3B,H3F3C, H6PD, HAAO, HABP2, HABP4, HACD1, HACD2, HACD3, HACD4, HACE1,HACL1, HADH, HADHA, HADHB, HAGH, HAGHL, HAL, HAMP, HAND1, HAND2, HAO1,HAO2, HAP1, HAPLN1, HAPLN2, HAPLN3, HAPLN4, HARBII, HARS, HARS2, HAS1,HAS2, HAS3, HASPIN, HAT1, HAUS1, HAUS2, HAUS3, HAUS4, HAUS5, HAUS6,HAUS7, HAUS8, HAVCR1, HAVCR2, HAX1, HBA1, HBA2, HBB, HBD, HBEl, HBEGF,HBG1, HBG2, HBM, HBP1, HBQ1, HBS1L, HBZ, HCAR1, HCAR2, HCAR3, HCCS,HCFC1, HCFC1R1, HCFC2, HCK, HCLS1, HCN1, HCN2, HCN3, HCN4, HCRT, HCRTR1,HCRTR2, HCST, HDAC1, HDAC10, HDAC11, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6,HDAC7, HDAC8, HDAC9, HDC, HDDC2, HDDC3, HDGF, HDGFL1, HDGFL2, HDGFL3,HDHD2, HDHD3, HDHD5, HDLBP, HDX, HEATR1, HEATR3, HEATR4, HEATR5A,HEATR5B, HEATR6, HEATR9, HEBP1, HEBP2, HECA, HECTD1, HECTD2, HECTD3,HECTD4, HECW1, HECW2, HEG1, HELB, HELLS, HELQ, HELT, HELZ, HELZ2, HEMGN,HEMK1, HENMT1, HEPACAM, HEPACAM2, HEPH, HEPHL1, HEPN1, HERC1, HERC2,HERC3, HERC4, HERC5, HERC6, HERPUDI, HERPUD2, HES1, HES2, HES3, HES4,HES5, HES6, HES7, HESX1, HEXA, HEXB, HEXDC, HEXIM1, HEXIM2, HEYl, HEY2,HEYL, HFE, HFE2, HFM1, HGD, HGF, HGFAC, HGH1, HGNC:18790, HGNC:24955,HGS, HGSNAT, HHAT, HHATL, HHEX, HHIP, HHIPL1, HHIPL2, HHLA1, HHLA2,HHLA3, HIBADH, HIBCH, HIC1, HIC2, HID1, HIF1A, HIF1AN, HIF3A, HIGD1A,HIGD1B, HIGD1C, HIGD2A, HIGD2B, HIKESHI, HILPDA, HINFP, HINT1, HINT2,HINT3, HIP1, HIP1R, HIPK1, HIPK2, HIPK3, HIPK4, HIRA, HIRIP3, HISTIHIA,HISTIHIB, HISTIHIC, HISTIHID, HISTIHIE, HISTIHIT, HIST1H2AA, HIST1H2AB,HIST1H2AC, HIST1H2AD, HIST1H2AE, HIST1H2AG, HIST1H2AH, HIST1H2AI,HIST1H2AJ, HIST1H2AK, HIST1H2AL, HIST1H2AM, HIST1H2BA, HIST1H2BB,HIST1H2BC, HIST1H2BD, HIST1H2BE, HIST1H2BF, HIST1H2BG, HIST1H2BH,HIST1H2BI, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BM, HIST1H2BN,HIST1H2BO, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F,HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J, HIST1H4A, HIST1H4B, HIST1H4C,HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4G, HIST1H4H, HIST1H4I, HIST1H4J,HIST1H4K, HIST1H4L, HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC,HIST2H2BE, HIST2H2BF, HIST2H3A, HIST2H3C, HIST2H3D, HIST2H3PS2,HIST2H4A, HIST2H4B, HIST3H2A, HIST3H2BB, HIST3H3, HIST4H4, HIVEP1,HIVEP2, HIVEP3, HJURP, HK1, HK2, HK3, HKDC1, HKR1, HLA-A, HLA-B, HLA-C,HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1,HLA-DQA2, HLA-DQB1, HLA-DQB2, HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4,HLA-DRB5, HLA-E, HLA-F, HLA-G, HLCS, HLF, HLTF, HLX, HM13, HM190170.1,HMBOXI, HMBS, HMCES, HMCN1, HMCN2, HMG20A, HMG20B, HMGA1, HMGA2, HMGB1,HMGB2, HMGB3, HMGB4, HMGCL, HMGCLL1, HMGCR, HMGCS1, HMGCS2, HMGN1,HMGN2, HMGN3, HMGN4, HMGN5, HMGXB3, HMGXB4, HMHB1, HMMR, HMOX1, HMOX2,HMSD, HMX1, HMX2, HMX3, HNF1A, HNF1B, HNF4A, HNF4G, HNMT, HNRNPA0,HNRNPA1, HNRNPA1L2, HNRNPA2B1, HNRNPA3, HNRNPAB, HNRNPC, HNRNPCL1,HNRNPCL2, HNRNPCL3, HNRNPCL4, HNRNPD, HNRNPDL, HNRNPF, HNRNPH1, HNRNPH2,HNRNPH3, HNRNPK, HNRNPL, HNRNPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1,HNRNPUL2, HNRNPUL2-BSCL2, HOGA1, HOMERI, HOMER2, HOMER3, HOMEZ, HOOK1,HOOK2, HOOK3, HOPX, HORMAD1, HORMAD2, HOXA1, HOXA10, HOXA11, HOXA13,HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXB1, HOXB13, HOXB2,HOXB3, HOXB4, HOXB5, HOXB6, HOXB7, HOXB8, HOXB9, HOXC10, HOXC11, HOXC12,HOXC13, HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXD1, HOXD10, HOXD11,HOXD12, HOXD13, HOXD3, HOXD4, HOXD8, HOXD9, HP, HP1BP3, HPCA, HPCAL1,HPCAL4, HPD, HPDL, HPF1, HPGD, HPGDS, HPN, HPR, HPRT1, HPS1, HPS3, HPS4,HPS5, HPS6, HPSE, HPSE2, HPX, HR, HRAS, HRASLS, HRASLS2, HRASLS5, HRC,HRCT1, HRG, HRH1, HRH2, HRH3, HRH4, HRK, HRNR, HS1BP3, HS2ST1, HS3ST1,HS3ST2, HS3ST3A1, HS3ST3B1, HS3ST4, HS3ST5, HS3ST6, HS6ST1, HS6ST2,HS6ST3, HSBP1, HSBP1L1, HSCB, HSD11B1, HSD11B1L, HSD11B2, HSD17B1,HSD17B10, HSD17B11, HSD17B12, HSD17B13, HSD17B14, HSD17B2, HSD17B3,HSD17B4, HSD17B6, HSD17B7, HSD17B8, HSD3B1, HSD3B2, HSD3B7, HSDL1,HSDL2, HSF1, HSF2, HSF2BP, HSF4, HSF5, HSFX1, HSFX2, HSFX3, HSFX4,HSFY1, HSFY2, HSH2D, HSP90AA1, HSP90AB1, HSP90B1, HSPA12A, HSPA12B,HSPA13, HSPA14, HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA4, HSPA4L, HSPA5,HSPA6, HSPA8, HSPA9, HSPB1, HSPB11, HSPB2, HSPB2-Cllorf52, HSPB3, HSPB6,HSPB7, HSPB8, HSPB9, HSPBAP1, HSPBP1, HSPD1, HSPE1, HSPE1-MOB4, HSPG2,HSPH1, HTATIP2, HTATSF1, HTD2, HTN1, HTN3, HTR1A, HTR1B, HTR1D, HTR1E,HTR1F, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR3C, HTR3D, HTR3E, HTR4,HTR5A, HTR6, HTR7, HTRA1, HTRA2, HTRA3, HTRA4, HTT, HUNK, HUS1, HUS1B,HUWEl, HVCN1, HYAL1, HYAL2, HYAL3, HYAL4, HYDIN, HYI, HYKK, HYLS1,HYOU1, HYPK, HYPM, IAH1, IAPP, IARS, IARS2, I1BA57, IBSP, IBTK, ICAl,ICA1L, ICAMI, ICAM2, ICAM3, ICAM4, ICAM5, ICEl, ICE2, ICK, ICMT, ICOS,ICOSLG, ID1, ID2, ID3, ID4, IDE, IDH1, IDH2, IDH3A, IDH3B, IDH3G, IDIl,IDI2, IDNK, IDO1, IDO2, IDS, IDUA, IER2, IER3, IER3IP1, IER5, IER5L,IFFO1, IFF02, IFI16, IFI27, IFI27L1, IFI27L2, IFI30, IFI35, IFI44,IFI44L, IFI6, IFIH1, IFIT1, IFIT1B, IFIT2, IFIT3, IFIT5, IFITMI,IFITM1O, IFITM2, IFITM3, IFITM5, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16,IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1,IFNAR2, IFNB1, IFNE, IFNG, IFNGR1, IFNGR2, IFNK, IFNL1, IFNL2, IFNL3,IFNL4, IFNLR1, IFNW1, IFRD1, IFRD2, IFT122, IFT140, IFT172, IFT20,IFT22, IFT27, IFT43, IFT46, IFT52, IFT57, IFT74, IFT80, IFT81, IFT88,IGBP1, IGDCC3, IGDCC4, IGF1, IGF1R, IGF2, IGF2BP1, IGF2BP2, IGF2BP3,IGF2R, IGFALS, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGFBP7,IGFBPL1, IGFL1, IGFL2, IGFL3, IGFL4, IGFLR1, IGFN1, IGHA1, IGHA2, IGHD,IGHD1-1, IGHD1-14, IGHD1-20, IGHD1-26, IGHD1-7, IGHDIOR15-1A,IGHD1OR15-1B, IGHD2-15, IGHD2-2, IGHD2-21, IGHD2-8, IGHD2OR15-2A,IGHD2OR15-2B, IGHD3-10, IGHD3-16, IGHD3-22, IGHD3-3, IGHD3-9,IGHD30R15-3A, IGHD30R15-3B, IGHD4-11, IGHD4-17, IGHD4-23, IGHD4-4,IGHD40R15-4A, IGHD40R15-4B, IGHD5-12, IGHD5-18, IGHD5-24, IGHD5-5,IGHD50R15-5A, IGHD50R15-5B, IGHD6-13, IGHD6-19, IGHD6-25, IGHD6-6,IGHD7-27, IGHE, IGHG1, IGHG2, IGHG3, IGHG4, IGHJ1, IGHJ2, IGHJ3, IGHJ4,IGHJ5, IGHJ6, IGHM, IGHMBP2, IGHV1-18, IGHV1-2, IGHV1-24, IGHV1-3,IGHV1-45, IGHV1-46, IGHV1-58, IGHV1-69, IGHV1OR15-1, IGHV1OR15-9,IGHV1OR21-1, IGHV2-26, IGHV2-5, IGHV2-70, IGHV2OR16-5, IGHV3-11,IGHV3-13, IGHV3-15, IGHV3-16, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30,IGHV3-33, IGHV3-35, IGHV3-38, IGHV3-43, IGHV3-48, IGHV3-49, IGHV3-53,IGHV3-64, IGHV3-66, IGHV3-7, IGHV3-72, IGHV3-73, IGHV3-74, IGHV30R15-7,IGHV30R16-10, IGHV30R16-12, IGHV30R16-13, IGHV30R16-8, IGHV30R16-9,IGHV4-28, IGHV4-31, IGHV4-34, IGHV4-39, IGHV4-4, IGHV4-59, IGHV4-61,IGHV4OR15-8, IGHV5-51, IGHV6-1, IGHV7-81, IGIP, IGKC, IGKJ1, IGKJ2,IGKJ3, IGKJ4, IGKJ5, IGKV1-12, IGKV1-16, IGKV1-17, IGKV1-27, IGKV1-33,IGKV1-37, IGKV1-39, IGKV1-5, IGKV1-6, IGKV1-8, IGKV1-9, IGKV1D-12,IGKV1D-13, IGKV1D-16, IGKV1D-17, IGKV1D-33, IGKV1D-37, IGKV1D-39,IGKV1D-42, IGKV1D-43, IGKV1D-8, IGKV1OR2-108, IGKV2-24, IGKV2-28,IGKV2-30, IGKV2-40, IGKV2D-24, IGKV2D-26, IGKV2D-28, IGKV2D-29,IGKV2D-30, IGKV2D-40, IGKV3-11, IGKV3-15, IGKV3-20, IGKV3-7, IGKV3D-11,IGKV3D-15, IGKV3D-20, IGKV3D-7, IGKV3OR2-268, IGKV4-1, IGKV5-2,IGKV6-21, IGKV6D-21, IGKV6D-41, IGLC1, IGLC2, IGLC3, IGLC7, IGLJ1,IGLJ2, IGLJ3, IGLJ4, IGLJ5, IGLJ6, IGLJ7, IGLL1, IGLL5, IGLON5,IGLV10-54, IGLV11-55, IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-50,IGLV1-51, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23, IGLV2-33, IGLV2-8,IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-22,IGLV3-25, IGLV3-27, IGLV3-32, IGLV3-9, IGLV4-3, IGLV4-60, IGLV4-69,IGLV5-37, IGLV5-45, IGLV5-48, IGLV5-52, IGLV6-57, IGLV7-43, IGLV7-46,IGLV8-61, IGLV9-49, IGSF1, IGSF10, IGSF11, IGSF21, IGSF22, IGSF23,IGSF3, IGSF5, IGSF6, IGSF8, IGSF9, IGSF9B, IHH, IK, IKBIP, IKBKB, IKBKE,IKBKG, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, IL10, IL1ORA, IL1ORB, IL11,IL11RA, IL12A, IL12B, IL12RB1, IL12RB2, IL13, IL13RA1, IL13RA2, IL15,IL15RA, IL16, IL17A, IL17B, IL17C, IL17D, IL17F, IL17RA, IL17RB, IL17RC,IL17RD, IL17RE, IL17REL, IL18, IL18BP, IL18R1, IL18RAP, IL19, ILlA,IL1B, IL1F10, IL1R1, IL1R2, IL1RAP, IL1RAPL1, IL1RAPL2, IL1RL1, IL1RL2,IL1RN, IL2, IL20, IL20RA, IL20RB, IL21, IL21R, IL22, IL22RA1, IL22RA2,IL23A, IL23R, IL24, IL25, IL26, IL27, IL27RA, IL2RA, IL2RB, IL2RG, IL3,IL31, IL31RA, IL32, IL33, IL34, IL36A, IL36B, IL36G, IL36RN, IL37,IL3RA, IL4, IL4I1, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL7R, IL9,IL9R, ILDR1, ILDR2, ILF2, ILF3, ILK, ILKAP, ILVBL, IMMP1L, IMMP2L, IMMT,IVP3, IMP4, IMPA1, IMPA2, IMPACT, IMPAD1, ITMPDH1, IMPDH2, IMPG1, IMPG2,INA, INAFM1, INAFM2, INAVA, INCA1, INCENP, INF2, ING1, ING2, ING3, ING4,ING5, INHA, INHBA, INHBB, INHBC, INHBE, INIP, INMT, INMT-MINDY4, IN080,INO80B, INO8OB-WBP1, INO80C, INO80D, INO80E, INPP1, INPP4A, INPP4B,INPP5A, INPP5B, INPP5D, INPP5E, INPP5F, INPP5J, INPP5K, INPPL1, INS,INSC, INSIGI, INSIG2, INS-IGF2, INSL3, INSL4, INSL5, INSL6, INSM1,INSM2, INSR, INSRR, INTS1, INTS10, INTS11, INTS12, INTS13, INTS14,INTS2, INTS3, INTS4, INTS5, INTS6, INTS6L, INTS7, INTS8, INTS9, INTU,INVS, IP6K1, IP6K2, IP6K3, IPCEF1, IPMK, IPO11, IPO13, IPO4, IPO5, IPO7,IPO8, IPO9, IPP, IPPK, IQANKI, IQCA1, IQCA1L, IQCB1, IQCC, IQCD, IQCE,IQCF1, IQCF2, IQCF3, IQCF5, IQCF6, IQCG, IQCH, IQCJ, IQCJ-SCHIP1, IQCK,IQCM, IQGAP1, IQGAP2, IQGAP3, IQSEC1, IQSEC2, IQSEC3, IQUB, IRAK1,IRAKIBPI, IRAK2, IRAK3, IRAK4, IREB2, IRF1, IRF2, IRF2BP1, IRF2BP2,IRF2BPL, IRF3, IRF4, IRF5, IRF6, IRF7, IRF8, IRF9, IRGC, IRGM, IRGQ,IRS1, IRS2, IRS4, IRX1, IRX2, IRX3, IRX4, IRX5, IRX6, ISCA1, ISCA2,ISCU, ISG15, ISG20, ISG20L2, ISL1, ISL2, ISLR, ISLR2, ISM1, ISM2, ISOC1,ISOC2, ISPD, IST1, ISX, ISYl, ISY1-RAB43, ISYNA1, ITCH, ITFG1, ITFG2,ITGA1, ITGA10, ITGA11, ITGA2, ITGA2B, ITGA3, ITGA4, ITGA5, ITGA6, ITGA7,ITGA8, ITGA9, ITGAD, ITGAE, ITGAL, ITGAM, ITGAV, ITGAX, ITGB1, ITGB1BP1,ITGB1BP2, ITGB2, ITGB3, ITGB3BP, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8,ITGBL1, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, ITK, ITLN1, ITLN2,ITM2A, ITM2B, ITM2C, ITPA, ITPK1, ITPKA, ITPKB, ITPKC, ITPR1, ITPR2,ITPR3, ITPRIP, ITPRIPL1, ITPRIPL2, ITSN1, ITSN2, IVD, IVL, IVNS1ABP,IWS1, IYD, IZUMO1, IZUMOIR, IZUMO2, IZUMO3, IZUMO4, JADE1, JADE2, JADE3,JAG1, JAG2, JAGN1, JAK1, JAK2, JAK3, JAKMIP1, JAKMIP2, JAKMIP3, JAM2,JAM3, JAML, JARID2, JAZF1, JCAD, JCHAIN, JDP2, JKAMP, JMJD1C, JMJD4,JMJD6, JMJD7, JMJD7-PLA2G4B, JMJD8, JMY, JOSD1, JOSD2, JPH1, JPH2, JPH3,JPH4, JPT1, JPT2, JRK, JRKL, JSRP1, JTB, JUN, JUNB, JUND, JUP, KAAG1,KALRN, KANK1, KANK2, KANK3, KANK4, KANSLI, KANSLIL, KANSL2, KANSL3,KANTR, KARS, KAT14, KAT2A, KAT2B, KAT5, KAT6A, KAT6B, KAT7, KAT8,KATNA1, KATNAL1, KATNAL2, KATNB1, KATNBL1, KAZALD1, KAZN, KBTBD11,KBTBD11-OT1, KBTBD12, KBTBD13, KBTBD2, KBTBD3, KBTBD4, KBTBD6, KBTBD7,KBTBD8, KCMF1, KCNA1, KCNA10, KCNA2, KCNA3, KCNA4, KCNA5, KCNA7, KCNAB1,KCNAB2, KCNAB3, KCNB1, KCNB2, KCNC1, KCNC2, KCNC3, KCNC4, KCND1, KCND2,KCND3, KCNE1, KCNElB, KCNE2, KCNE3, KCNE4, KCNE5, KCNF1, KCNG1, KCNG2,KCNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4, KCNH5, KCNH6, KCNH7, KCNH8,KCNIP1, KCNIP2, KCNIP3, KCNIP4, KCNJ1, KCNJ10, KCNJ11, KCNJ12, KCNJ13,KCNJ14, KCNJ15, KCNJ16, KCNJ18, KCNJ2, KCNJ3, KCNJ4, KCNJ5, KCNJ6,KCNJ8, KCNJ9, KCNK1, KCNK10, KCNK12, KCNK13, KCNK15, KCNK16, KCNK17,KCNK18, KCNK2, KCNK3, KCNK4, KCNK5, KCNK6, KCNK7, KCNK9, KCNMA1, KCNMB1,KCNMB2, KCNMB3, KCNMB4, KCNN1, KCNN2, KCNN3, KCNN4, KCNQ1, KCNQ2, KCNQ3,KCNQ4, KCNQ5, KCNRG, KCNS1, KCNS2, KCNS3, KCNT1, KCNT2, KCNU1, KCNV1,KCNV2, KCP, KCTD1, KCTD10, KCTD11, KCTD12, KCTD13, KCTD14, KCTD15,KCTD16, KCTD17, KCTD18, KCTD19, KCTD2, KCTD20, KCTD21, KCTD3, KCTD4,KCTD5, KCTD6, KCTD7, KCTD8, KCTD9, KDELC1, KDELC2, KDELR1, KDELR2,KDELR3, KDF1, KDM1A, KDM1B, KDM2A, KDM2B, KDM3A, KDM3B, KDM4A, KDM4B,KDM4C, KDM4D, KDM4E, KDM4F, KDM5A, KDM5B, KDM5C, KDM5D, KDM6A, KDM6B,KDM7A, KDM8, KDR, KDSR, KEAP1, KEL, KERA, KF459570.1, KHDC1, KHDC1L,KHDC3L, KHDRBS1, KHDRBS2, KHDRBS3, KHK, KHNYN, KHSRP, KIAA0040,KIAA0100, KIAA0141, KIAA0232, KIAA0319, KIAA0319L, KIAA0355, KIAA0368,KIAA0391, KIAA0408, KIAA0513, KIAA0556, KIAA0586, KIAA0753, KIAA0825,KIAA0895, KIAA0895L, KIAA0907, KIAA0930, KIAA1024, KIAA1024L, KIAA1107,KIAA1109, KIAA1143, KIAA1147, KIAA1161, KIAA1191, KIAA1210, KIAA1211,KIAA1211L, KIAA1217, KIAA1257, KIAA1324, KIAA1324L, KIAA1328, KIAA1456,KIAA1468, KIAA1522, KIAA1524, KIAA1549, KIAA1549L, KIAA1551, KIAA1586,KIAA1614, KIAA1644, KIAA1671, KIAA1683, KIAA1755, KIAA1841, KIAA1958,KIAA2012, KIAA2013, KIAA2026, KIDINS220, KIF11, KIF12, KIF13A, KIF13B,KIF14, KIF15, KIF16B, KIF17, KIF18A, KIF18B, KIF19, KIF1A, KIF1B,KIF1BP, KIF1C, KIF20A, KIF20B, KIF21A, KIF21B, KIF22, KIF23, KIF24,KIF25, KIF26A, KIF26B, KIF27, KIF2A, KIF2B, KIF2C, KIF3A, KIF3B, KIF3C,KIF4A, KIF4B, KIF5A, KIF5B, KIF5C, KIF6, KIF7, KIF9, KIFAP3, KIFC1,KIFC2, KIFC3, KIN, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A,KIR2DL5B, KIR2DP1, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1,KIR3DL2, KIR3DL3, KIR3DP1, KIR3DS1, KIR3DX1, KIRREL1, KIRREL2, KIRREL3,KISS1, KISS1R, KIT, KITLG, KIZ, KL, KLB, KLC1, KLC2, KLC3, KLC4, KLF1,KLF10, KLF11, KLF12, KLF13, KLF14, KLF15, KLF16, KLF17, KLF18, KLF2,KLF3, KLF4, KLF5, KLF6, KLF7, KLF8, KLF9, KLHDC1, KLHDC1O, KLHDC2,KLHDC3, KLHDC4, KLHDC7A, KLHDC7B, KLHDC8A, KLHDC8B, KLHDC9, KLHL1,KLHL10, KLHL11, KLHL12, KLHL13, KLHL14, KLHL15, KLHL17, KLHL18, KLHL2,KLHL20, KLHL21, KLHL22, KLHL23, KLHL24, KLHL25, KLHL26, KLHL28, KLHL29,KLHL3, KLHL30, KLHL31, KLHL32, KLHL33, KLHL34, KLHL35, KLHL36, KLHL38,KLHL4, KLHL40, KLHL41, KLHL42, KLHL5, KLHL6, KLHL7, KLHL8, KLHL9, KLK1,KLK10, KLK11, KLK12, KLK13, KLK14, KLK15, KLK2, KLK3, KLK4, KLK5, KLK6,KLK7, KLK8, KLK9, KLKB1, KLLN, KLRB1, KLRC1, KLRC2, KLRC3, KLRC4,KLRC4-KLRK1, KLRD1, KLRF1, KLRF2, KLRG1, KLRG2, KLRK1, KMO, KMT2A,KMT2B, KMT2C, KMT2D, KMT2E, KMT5A, KMT5B, KMT5C, KNCN, KNDC1, KNG1,KNL1, KNOP1, KNSTRN, KNTC1, KP420437.1, KP420437.2, KP420437.3,KP420439.1, KP420440.1, KP420440.2, KP420440.3, KP420440.4, KP420440.5,KP420440.6, KP420440.7, KP420440.8, KP420440.9, KP420441.1, KP420441.2,KP420441.3, KP420441.4, KP420441.5, KP420442.2, KP420442.3, KP420443.1,KP420444.1, KP420444.2, KP420444.3, KP420444.4, KP420444.5, KP420444.6,KP420444.7, KP420446.1, KP420446.2, KPNA1, KPNA2, KPNA3, KPNA4, KPNA5,KPNA6, KPNA7, KPNB1, KPRP, KPTN, KRAS, KRBA1, KRBA2, KRBOX1, KRBOX4,KRCC1, KREMEN1, KREMEN2, KRI1, KRIT1, KRR1, KRT1, KRT10, KRT12, KRT13,KRT14, KRT15, KRT16, KRT17, KRT18, KRT19, KRT2, KRT20, KRT222, KRT23,KRT24, KRT25, KRT26, KRT27, KRT28, KRT3, KRT31, KRT32, KRT33A, KRT33B,KRT34, KRT35, KRT36, KRT37, KRT38, KRT39, KRT4, KRT40, KRT5, KRT6A,KRT6B, KRT6C, KRT7, KRT71, KRT72, KRT73, KRT74, KRT75, KRT76, KRT77,KRT78, KRT79, KRT8, KRT80, KRT81, KRT82, KRT83, KRT84, KRT85, KRT86,KRT9, KRTAP1O-1, KRTAP1O-10, KRTAP10-11, KRTAP10-12, KRTAP10-2,KRTAP10-3, KRTAP10-4, KRTAP10-5, KRTAP10-6, KRTAP10-7, KRTAP10-8,KRTAP10-9, KRTAP1-1, KRTAP11-1, KRTAP12-1, KRTAP12-2, KRTAP12-3,KRTAP12-4, KRTAP1-3, KRTAP13-1, KRTAP13-2, KRTAP13-3, KRTAP13-4,KRTAP1-4, KRTAP1-5, KRTAP15-1, KRTAP16-1, KRTAP17-1, KRTAP19-1,KRTAP19-2, KRTAP19-3, KRTAP19-4, KRTAP19-5, KRTAP19-6, KRTAP19-7,KRTAP19-8, KRTAP20-1, KRTAP20-2, KRTAP20-3, KRTAP20-4, KRTAP2-1,KRTAP21-1, KRTAP21-2, KRTAP21-3, KRTAP2-2, KRTAP22-1, KRTAP22-2,KRTAP2-3, KRTAP23-1, KRTAP2-4, KRTAP24-1, KRTAP25-1, KRTAP26-1,KRTAP27-1, KRTAP29-1, KRTAP3-1, KRTAP3-2, KRTAP3-3, KRTAP4-1, KRTAP4-11,KRTAP4-12, KRTAP4-16, KRTAP4-2, KRTAP4-3, KRTAP4-4, KRTAP4-5, KRTAP4-6,KRTAP4-7, KRTAP4-8, KRTAP4-9, KRTAP5-1, KRTAP5-10, KRTAP5-11, KRTAP5-2,KRTAP5-3, KRTAP5-4, KRTAP5-5, KRTAP5-6, KRTAP5-7, KRTAP5-8, KRTAP5-9,KRTAP6-1, KRTAP6-2, KRTAP6-3, KRTAP7-1, KRTAP8-1, KRTAP9-1, KRTAP9-2,KRTAP9-3, KRTAP9-4, KRTAP9-6, KRTAP9-7, KRTAP9-8, KRTAP9-9, KRTCAP2,KRTCAP3, KRTDAP, KSR1, KSR2, KTI12, KTN1, KU645196.1, KU645196.2,KU645196.3, KU645196.4, KU645196.5, KU645196.6, KU645196.7, KU645196.8,KU645196.9, KU645197.1, KU645197.2, KU645197.3, KU645197.4, KU645197.5,KU645198.1, KXD1, KY, KYAT1, KYAT3, KYNU, LlCAM, L1TD1, L2HGDH,L34079.1, L3HYPDH, L3MBTL1, L3MBTL2, L3MBTL3, L3MBTL4, LACC1, LACRT,LACTB, LACTB2, LACTBL1, LAD1, LAG3, LAGE3, LAIR1, LAIR2, LALBA, LAMA1,LAMA2, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMB3, LAMB4, LAMC1, LAMC2,LAMC3, LAMP1, LAMP2, LAMP3, LAMP5, LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4,LAMTOR5, LANCL1, LANCL2, LANCL3, LAP3, LAPTM4A, LAPTM4B, LAPTM5, LARGE1,LARGE2, LARP1, LARPIB, LARP4, LARP4B, LARP6, LARP7, LARS, LARS2, LAS1L,LASP1, LAT, LAT2, LATS1, LATS2, LAX1, LAYN, LBH, LBHD1, LBP, LBR, LBX1,LBX2, LCA5, LCA5L, LCAT, LCE1A, LCE1B, LCE1C, LCE1D, LCE1E, LCE1F,LCE2A, LCE2B, LCE2C, LCE2D, LCE3A, LCE3B, LCE3C, LCE3D, LCE3E, LCE4A,LCE5A, LCE6A, LCK, LCLAT1, LCMT1, LCMT2, LCN1, LCN10, LCN12, LCN15,LCN2, LCN6, LCN8, LCN9, LCNL1, LCOR, LCORL, LCP1, LCP2, LCT, LCTL, LDAH,LDB1, LDB2, LDB3, LDHA, LDHAL6A, LDHAL6B, LDHB, LDHC, LDHD, LDLR,LDLRAD1, LDLRAD2, LDLRAD3, LDLRAD4, LDLRAP1, LDOC1, LEAP2, LECT2, LEF1,LEFTY1, LEFTY2, LEKR1, LELP1, LEMD1, LEMD2, LEMD3, LENEP, LENG1, LENG8,LENG9, LEO1, LEP, LEPR, LEPROT, LEPROTL1, LETM1, LETM2, LETMD1, LEUTX,LEXM, LFNG, LGALS1, LGALS12, LGALS13, LGALS14, LGALS16, LGALS2, LGALS3,LGALS3BP, LGALS4, LGALS7, LGALS7B, LGALS8, LGALS9, LGALS9B, LGALS9C,LGALSL, LGI1, LGI2, LGI3, LGI4, LGMN, LGR4, LGR5, LGR6, LGSN, LHB,LHCGR, LHFPL1, LHFPL2, LHFPL3, LHFPL4, LHFPL5, LHFPL6, LHPP, LHX1, LHX2,LHX3, LHX4, LHX5, LHX6, LHX8, LHX9, LIAS, LIF, LIFR, LIG1, LIG3, LIG4,LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB1, LILRB2, LILRB3,LILRB4, LILRB5, LIM2, LIMA1, LIMCH1, LIMD1, LIMD2, LIME1, LIMK1, LIMK2,LIMS1, LIMS2, LIMS3, LIMS4, LIN28A, LIN28B, LIN37, LIN52, LIN54, LIN7A,LIN7B, LIN7C, LIN9, LINC00094, LINC00116, LINC00282, LINC00672,LINC00675, LINC00694, LINC00854, LINC00890, LINC00959, LINC01125,LINC01556, LINC02210-CRHR1, LINGO1, LING02, LINGO3, LINGO4, LINS1, LIPA,LIPC, LIPE, LIPF, LIPG, LIPH, LIPI, LIPJ, LIPK, LIPM, LIPN, LIPT1,LIPT2, LITAF, LIX1, LIX1L, LKAAEAR1, LLGL1, LLGL2, LLPH, LMAN1, LMAN1L,LMAN2, LMAN2L, LMBR1, LMBR1L, LMBRD1, LMBRD2, LMCD1, LMF1, LMF2, LMLN,LMNA, LMNB1, LMNB2, LMNTD1, LMNTD2, LMO1, LMO2, LMO3, LMO4, LMO7,LMO7DN, LMOD1, LMOD2, LMOD3, LMTK2, LMTK3, LMX1A, LMX1B, LNP1, LNPEP,LNPK, LNX1, LNX2, LO000005.1, LONP1, LONP2, LONRF1, LONRF2, LONRF3, LOR,LOX, LOXHD1, LOXL1, LOXL2, LOXL3, LOXL4, LPA, LPAR1, LPAR2, LPAR3,LPAR4, LPAR5, LPAR6, LPCAT1, LPCAT2, LPCAT3, LPCAT4, LPGAT1, LPIN1,LPIN2, LPIN3, LPL, LPO, LPP, LPXN, LRAT, LRBA, LRCH1, LRCH2, LRCH3,LRCH4, LRCOL1, LRFN1, LRFN2, LRFN3, LRFN4, LRFN5, LRG1, LRGUK, LRIF1,LRIG1, LRIG2, LRIG3, LRIT1, LRIT2, LRIT3, LRMDA, LRMP, LRP1, LRP10,LRP11, LRP12, LRP1B, LRP2, LRP2BP, LRP3, LRP4, LRP5, LRP5L, LRP6, LRP8,LRPAP1, LRPPRC, LRR1, LRRC1, LRRC10, LRRC10B, LRRC14, LRRC14B, LRRC15,LRRC17, LRRC18, LRRC19, LRRC2, LRRC20, LRRC23, LRRC24, LRRC25, LRRC26,LRRC27, LRRC28, LRRC29, LRRC3, LRRC30, LRRC31, LRRC32, LRRC34, LRRC36,LRRC37A, LRRC37A2, LRRC37A3, LRRC37B, LRRC38, LRRC39, LRRC3B, LRRC3C,LRRC4, LRRC40, LRRC41, LRRC42, LRRC43, LRRC45, LRRC46, LRRC47, LRRC49,LRRC4B, LRRC4C, LRRC52, LRRC53, LRRC55, LRRC56, LRRC57, LRRC58, LRRC59,LRRC6, LRRC61, LRRC63, LRRC66, LRRC69, LRRC7, LRRC70, LRRC71, LRRC72,LRRC73, LRRC74A, LRRC74B, LRRC75A, LRRC75B, LRRC8A, LRRC8B, LRRC8C,LRRC8D, LRRC8E, LRRC9, LRRCC1, LRRD1, LRRFIP1, LRRFIP2, LRRIQ1, LRRIQ3,LRRIQ4, LRRK1, LRRK2, LRRN1, LRRN2, LRRN3, LRRN4, LRRN4CL, LRRTM1,LRRTM2, LRRTM3, LRRTM4, LRSAM1, LRTM1, LRTM2, LRTOMT, LRWD1, LSAMP,LSG1, LSM1, LSM10, LSM11, LSM12, LSM14A, LSM14B, LSM2, LSM3, LSM4, LSM5,LSM6, LSM7, LSM8, LSMEM1, LSMEM2, LSP1, LSR, LSS, LST1, LTA, LTA4H, LTB,LTB4R, LTB4R2, LTBP1, LTBP2, LTBP3, LTBP4, LTBR, LTC4S, LTF, LTK, LTN1,LTV1, LUC7L, LUC7L2, LUC7L3, LUM, LURAP1, LURAP1L, LUZP1, LUZP2, LUZP4,LUZP6, LVRN, LXN, LY6D, LY6E, LY6G5B, LY6G5C, LY6G6C, LY6G6D, LY6G6E,LY6G6F, LY6H, LY6K, LY6L, LY75, LY75-CD302, LY86, LY9, LY96, LYAR, LYG1,LYG2, LYL1, LYN, LYNX1, LYPD1, LYPD2, LYPD3, LYPD4, LYPD5, LYPD6,LYPD6B, LYPD8, LYPLA1, LYPLA2, LYPLAL1, LYRM1, LYRM2, LYRM4, LYRM7,LYRM9, LYSMD1, LYSMD2, LYSMD3, LYSMD4, LYST, LYVE1, LYZ, LYZL1, LYZL2,LYZL4, LYZL6, LZIC, LZTFL1, LZTR1, LZTS1, LZTS2, LZTS3, M1AP, M6PR,MAATS1, MAB21L1, MAB21L2, MAB21L3, MACC1, MACF1, MACROD1, MACROD2,MAD1L1, MAD2L1, MAD2L1BP, MAD2L2, MADCAM1, MADD, MAEA, MAEL, MAF, MAF1,MAFA, MAFB, MAFF, MAFG, MAFK, MAG, MAGEA1, MAGEA10, MAGEA11, MAGEA12,MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA6, MAGEA8, MAGEA9, MAGEA9B,MAGEB1, MAGEB10, MAGEB16, MAGEB17, MAGEB18, MAGEB2, MAGEB3, MAGEB4,MAGEB5, MAGEB6, MAGEB6P1, MAGEC1, MAGEC2, MAGEC3, MAGED1, MAGED2,MAGED4, MAGED4B, MAGEE1, MAGEE2, MAGEFI, MAGEHI, MAGEL2, MAGI1, MAGI2,MAGI3, MAGIX, MAGOH, MAGOHB, MAGT1, MAIP1, MAJIN, MAK, MAK16, MAL, MAL2,MALL, MALRD1, MALSU1, MALT1, MAMDC2, MAMDC4, MAML1, MAML2, MAML3,MAMLD1, MAMSTR, MAN1A1, MAN1A2, MAN1B1, MAN1C1, MAN2A1, MAN2A2, MAN2B1,MAN2B2, MAN2C1, MANBA, MANBAL, MANEA, MANEAL, MANF, MANSCI, MANSC4,MAOA, MAOB, MAP10, MAP1A, MAP1B, MAP1LC3A, MAP1LC3B, MAP1LC3B2,MAP1LC3C, MAPlS, MAP2, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAP2K6,MAP2K7, MAP3K1, MAP3K10, MAP3K11, MAP3K12, MAP3K13, MAP3K14, MAP3K15,MAP3K19, MAP3K2, MAP3K20, MAP3K21, MAP3K3, MAP3K4, MAP3K5, MAP3K6,MAP3K7, MAP3K7CL, MAP3K8, MAP3K9, MAP4, MAP4K1, MAP4K2, MAP4K3, MAP4K4,MAP4K5, MAP6, MAP6D1, MAP7, MAP7D1, MAP7D2, MAP7D3, MAP9, MAPK1, MAPK10,MAPK11, MAPK12, MAPK13, MAPK14, MAPK15, MAPK1IP1L, MAPK3, MAPK4, MAPK6,MAPK7, MAPK8, MAPK8IP1, MAPK8IP2, MAPK8IP3, MAPK9, MAPKAP1, MAPKAPK2,MAPKAPK3, MAPKAPK5, MAPKBP1, MAPREl, MAPRE2, MAPRE3, MAPT, MARC1, MARC2,MARCHI, MARCH10, MARCH11, MARCH2, MARCH3, MARCH4, MARCH5, MARCH6,MARCH7, MARCH8, MARCH9, MARCKS, MARCKSL1, MARCO, MARF1, MARK1, MARK2,MARK3, MARK4, MARS, MARS2, MARVELD1, MARVELD2, MARVELD3, MAS1, MAS1L,MASP1, MASP2, MAST1, MAST2, MAST3, MAST4, MASTL, MAT1A, MAT2A, MAT2B,MATK, MATN1, MATN2, MATN3, MATN4, MATR3, MAU2, MAVS, MAX, MAZ, MB,MB21D1, MB21D2, MBD1, MBD2, MBD3, MBD3L1, MBD3L2, MBD3L2B, MBD3L3,MBD3L4, MBD3L5, MBD4, MBD5, MBD6, MBIP, MBL2, MBLAC1, MBLAC2, MBNL1,MBNL2, MBNL3, MBOAT1, MBOAT2, MBOAT4, MBOAT7, MBP, MBTD1, MBTPS1,MBTPS2, MC1R, MC2R, MC3R, MC4R, MC5R, MCAM, MCAT, MCC, MCCC1, MCCC2,MCCD1, MCEE, MCEMP1, MCF2, MCF2L, MCF2L2, MCFD2, MCHR1, MCHR2, MCIDAS,MCL1, MCM10, MCM2, MCM3, MCM3AP, MCM4, MCM5, MCM6, MCM7, MCM8, MCM9,MCMBP, MCMDC2, MCOLN1, MCOLN2, MCOLN3, MCPH1, MCRIP1, MCRIP2, MCRS1,MCTP1, MCTP2, MCTS1, MCU, MCUB, MCUR1, MDC1, MDFI, MDFIC, MDFIC2, MDGA1,MDGA2, MDH1, MDH1B, MDH2, MDK, MDM1, MDM2, MDM4, MDN1, MDP1, MDS2, ME1,ME2, ME3, MEA1, MEAF6, MECOM, MECP2, MECR, MED1, MED10, MED11, MED12,MED12L, MED13, MED13L, MED14, MED14OS, MED15, MED16, MED17, MED18,MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED28,MED29, MED30, MED31, MED4, MED6, MED7, MED8, MED9, MEDAG, MEF2A, MEF2B,MEF2C, MEF2D, MEFV, MEGF10, MEGF11, MEGF6, MEGF8, MEGF9, MEIl, MEI4,MEIG1, MEIKIN, MEIOB, MEIOC, MEIS1, MEIS2, MEIS3, MELK, MELTF, MEMO1,MEN1, MEOX1, MEOX2, MEPlA, MEP1B, MEPCE, MEPE, MERTK, MESD, MESP1,MESP2, MEST, MET, METAP1, METAPlD, METAP2, METRN, METRNL, METTL1,METTL11B, METTL12, METTL13, METTL14, METTL15, METTL16, METTL17, METTL18,METTL21A, METTL21C, METTL22, METTL23, METTL24, METTL25, METTL26,METTL27, METTL2A, METTL2B, METTL3, METTL4, METTL5, METTL6, METTL7A,METTL7B, METTL8, METTL9, MEX3A, MEX3B, MEX3C, MEX3D, MFAP1, MFAP2,MFAP3, MFAP3L, MFAP4, MFAP5, MFF, MFGE8, MFHAS1, MIFN1, MFN2, MFNG,MFRP, MFSD1, MFSD10, MFSD11, MFSD12, MFSD13A, MFSD14A, MFSD14B, MFSD14C,MFSD2A, MFSD2B, MFSD3, MFSD4A, MFSD4B, MFSD5, MFSD6, MFSD6L, MFSD7,MFSD8, MFSD9, MGA, MGAM, MGAM2, MGARP, MGAT1, MGAT2, MGAT3, MGAT4A,MGAT4B, MGAT4C, MGAT4D, MGAT5, MGAT5B, MGEA5, MGLL, MGME1, MGMT, MGP,MGRN1, MGST1, MGST2, MGST3, MIA, MIA3, MIA-RAB4B, MIB1, MIB2, MICA,MICAL1, MICAL2, MICAL3, MICALCL, MICALL1, MICALL2, MICB, MICU1, MICU2,MICU3, MID1, MID1IP1, MID2, MIDN, MIEF1, MIEF2, MIEN1, MIER1, MIER2,MIER3, MIF, MIF4GD, MIGA1, MIGA2, MIIP, MILR1, MINDY1, MINDY2, MINDY3,MINDY4, MINDY4B, MINK1, MINOS1, MINOS1-NBL1, MINPP1, MIOS, MIOX, MIP,MIPEP, MIPOL1, MIS12, MIS18A, MIS18BP1, MISP, MISP3, MITD1, MITF, MIXL1,MKI67, MKKS, MKL1, MKL2, MKLN1, MKNK1, MKNK2, MKRN1, MKRN2, MKRN2OS,MKRN3, MKS1, MKX, MLANA, MLC1, MLEC, MLF1, MLF2, MLH1, MLH3, MLIP, MLKL,MLLT1, MLLT10, MLLT11, MLLT3, MLLT6, MLN, MLNR, MLPH, MLST8, MLX, MLXIP,MLXIPL, MLYCD, MMAA, MMAB, MMACHC, MMADHC, MMD, MMD2, MME, MMEL1, MMGT1,MMP1, MMP10, MMP11, MMP12, MMPP13, MMP14, MMP15, MMP16, MMP17, MMP19,MMP2, MMP20, MMP21, MMP23B, MMP24, MMP24-AS1, MMP25, MMP26, MMP27,MMP28, MMP3, MMP7, MMP8, MMP9, MMRN1, MMRN2, MMS19, MMS22L, MN1, MNAT 1,MND1, MNDA, MNS1, MNT, MNX1, MOAP1, MOB1A, MOB1B, MOB2, MOB3A, MOB3B,MOB3C, MOB4, MOBP, MOCOS, MOCS1, MOCS2, MOCS3, MOG, MOGATI, MOGAT2,MOGAT3, MOGS, MOK, MON1A, MON1B, MON2, MORC1, MORC2, MORC3, MORC4,MORF4L1, MORF4L2, MORN1, MORN2, MORN3, MORN4, MORN5, MOS, MOSPD1,MOSPD2, MOSPD3, MOV10, MOV10L1, MOXD1, MPC1, MPC1L, MPC2, MPDU1, MPDZ,MPEG1, MPG, MPHOSPH10, MPHOSPH6, MPHOSPH8, MPHOSPH9, MPI, MPIG6B, MPL,MPLKIP, MPND, MPO, MPP1, MPP2, MPP3, MPP4, MPP5, MPP6, MPP7, MPPEl,MPPED1, MPPED2, MPRIP, MPST, MPV17, MPV17L, MPV17L2, MPZ, MPZL1, MPZL2,MPZL3, MR1, MRAP, MRAP2, MRAS, MRC1, MRC2, MRE11, MREG, MRFAP1,MRFAP1L1, MRGBP, MRGPRD, MRGPRE, MRGPRF, MRGPRG, MRGPRX1, MRGPRX2,MRGPRX3, MRGPRX4, MRIl, MRLN, MRM1, MRM2, MRM3, MRNIP, MRO, MROH1,MROH2A, MROH2B, MROH5, MROH6, MROH7, MROH7-TTC4, MROH8, MROH9, MRPL1,MRPL10, MRPL11, MRPL12, MRPL13, MRPL14, MRPL15, MRPL16, MRPL17, MRPL18,MRPL19, MRPL2, MRPL20, MRPL21, MRPL22, MRPL23, MRPL24, MRPL27, MRPL28,MRPL3, MRPL30, MRPL32, MRPL33, MRPL34, MRPL35, MRPL36, MRPL37, MRPL38,MRPL39, MRPL4, MRPL40, MRPL41, MRPL42, MRPL43, MRPL44, MRPL45, MRPL46,MRPL47, MRPL48, MRPL49, MRPL50, MRPL51, MRPL52, MRPL53, MRPL54, MRPL55,MRPL57, MRPL58, MRPL9, MRPS10, MRPS11, MRPS12, MRPS14, MRPS15, MRPS16,MRPS17, MRPS18A, MRPS18B, MRPS18C, MRPS2, MRPS21, MRPS22, MRPS23,MRPS24, MRPS25, MRPS26, MRPS27, MRPS28, MRPS30, MRPS31, MRPS33, MRPS34,MRPS35, MRPS36, MRPS5, MRPS6, MRPS7, MRPS9, MRRF, MRS2, MRTO4, MRVIl,MS4A1, MS4A10, MS4A12, MS4A13, MS4A14, MS4A15, MS4A2, MS4A3, MS4A4A,MS4A4E, MS4A5, MS4A6A, MS4A6E, MS4A7, MS4A8, MSANTD1, MSANTD2, MSANTD3,MSANTD3-TMEFF1, MSANTD4, MSC, MSGN1, MSH2, MSH3, MSH4, MSH5,MSH5-SAPCD1, MSH6, MSI1, MSI2, MSL1, MSL2, MSL3, MSLN, MSLNL, MSMB,MSMO1, MSMP, MSN, MSR1, MSRA, MSRB1, MSRB2, MSRB3, MSS51, MST1, MST1R,MSTN, MSTO1, MSX1, MSX2, MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1IL1,MT1M, MT1X, MT2A, MT3, MT4, MTA1, MTA2, MTA3, MTAP, MT-ATP6, MT-ATP8,MTBP, MTCH1, MTCH2, MTCL1, MT-CO1, MT-C02, MT-C03, MTCP1, MT-CYB, MTDH,MTERF1, MTERF2, MTERF3, MTERF4, MTF1, MTF2, MTFMT, MTFP1, MTFR1, MTFR1L,MTFR2, MTG1, MTG2, MTHFD1, MTHFD1L, MTHFD2, MTHFD2L, MTHFR, MTHFS,MTHFSD, MTIF2, MTIF3, MTM1, MTMR1, MTMR10, MTMR11, MTMR12, MTMR14,MTMR2, MTMR3, MTMR4, MTMR6, MTMR7, MTMR8, MTMR9, MT-ND1, MT-ND2, MT-ND3,MT-ND4, MT-ND4L, MT-ND5, MT-ND6, MTNR1A, MTNR1B, MTO1, MTOR, MTPAP,MTPN, MTR, MTRF1, MTRF1L, MTRNR2L1, MTRNR2L10, MTRNR2L11, MTRNR2L12,MTRNR2L13, MTRNR2L3, MTRNR2L4, MTRNR2L5, MTRNR2L6, MTRNR2L7, MTRNR2L8,MTRR, MTSS1, MTSS1L, MTTP, MTURN, MTUS1, MTUS2, MTX1, MTX2, MTX3, MUC1,MUC12, MUC13, MUC15, MUC16, MUC17, MUC2, MUC20, MUC21, MUC22, MUC3A,MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUCL1, MUL1, MUM1, MUM1L1, MUS81, MUSK,MUSTN1, MUT, MUTYH, MVB12A, MVB12B, MVD, MVK, MVP, MX1, MX2, MXD1, MXD3,MXD4, MXIl, MXRA5, MXRA7, MXRA8, MYADM, MYADML2, MYB, MYBBPlA, MYBL1,MYBL2, MYBPC1, MYBPC2, MYBPC3, MYBPH, MYBPHL, MYC, MYCBP, MYCBP2,MYCBPAP, MYCL, MYCN, MYCT1, MYD88, MYDGF, MYEF2, MYEOV, MYF5, MYF6,MYH1, MYH10, MYH11, MYH13, MYH14, MYH15, MYH2, MYH3, MYH4, MYH6, MYH7,MYH7B, MYH8, MYH9, MYL1, MYL10, MYL12A, MYL12B, MYL2, MYL3, MYL4, MYL5,MYL6, MYL6B, MYL7, MYL9, MYLIP, MYLK, MYLK2, MYLK3, MYLK4, MYLPF, MYMK,MYMX, MYNN, MYO10, MYO15A, MYO15B, MYO16, MYO18A, MYO18B, MYO19, MYO1A,MYO1B, MYO1C, MYO1D, MYO1E, MYO1F, MYO1G, MYO1H, MYO3A, MYO3B, MYO5A,MYO5B, MYO5C, MYO6, MYO7A, MYO7B, MYO9A, MYO9B, MYOC, MYOCD, MYOCOS,MYOD1, MYOF, MYOG, MYOM1, MYOM2, MYOM3, MYOT, MYOZ1, MYOZ2, MYOZ3, MYPN,MYPOP, MYRF, MYRFL, MYRIP, MYSM1, MYT1, MYT1L, MYZAP, MZB1, MZF1, MZT1,MZT2A, MZT2B, N4BP1, N4BP2, N4BP2L1, N4BP2L2, N4BP3, N6AMT1, NAA10,NAA11, NAA15, NAA16, NAA20, NAA25, NAA30, NAA35, NAA38, NAA40, NAA50,NAA60, NAAA, NAALAD2, NAALADL1, NAALADL2, NAB1, NAB2, NABP1, NABP2,NACA, NACA2, NACAD, NACC1, NACC2, NADK, NADK2, NADSYN1, NAE1, NAF1,NAGA, NAGK, NAGLU, NAGPA, NAGS, NAIF1, NAIP, NALCN, NAMPT, NANOG,NANOGNB, NANOGP8, NANOSI, NANOS2, NANOS3, NANP, NANS, NAP1L1, NAP1L2,NAP1L3, NAP1L4, NAP1L5, NAPA, NAPB, NAPEPLD, NAPG, NAPRT, NAPSA, NARF,NARFL, NARS, NARS2, NASP, NAT1, NAT10, NAT14, NAT16, NAT2, NAT6, NAT8,NAT8B, NAT8L, NAT9, NATD1, NAV1, NAV2, NAV3, NAXD, NAXE, NBAS, NBDY,NBEA, NBEAL1, NBEAL2, NBL1, NBN, NBPF1, NBPF10, NBPF11, NBPF12, NBPF14,NBPF15, NBPF19, NBPF20, NBPF26, NBPF3, NBPF4, NBPF6, NBPF9, NBR1, NCALD,NCAM1, NCAM2, NCAN, NCAPD2, NCAPD3, NCAPG, NCAPG2, NCAPH, NCAPH2, NCBP1,NCBP2, NCBP2-AS2, NCBP2L, NCBP3, NCCRP1, NCDN, NCEH1, NCF1, NCF2, NCF4,NCK1, NCK2, NCKAP1, NCKAP1L, NCKAP5, NCKAP5L, NCKIPSD, NCL, NCLN, NCMAP,NCOA1, NCOA2, NCOA3, NCOA4, NCOA5, NCOA6, NCOA7, NCOR1, NCOR2, NCR1,NCR2, NCR3, NCR3LG1, NCS1, NCSTN, NDC1, NDC80, NDE1, NDEL1, NDFIP1,NDFIP2, NDN, NDNF, NDOR1, NDP, NDRG1, NDRG2, NDRG3, NDRG4, NDST1, NDST2,NDST3, NDST4, NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFA2,NDUFA3, NDUFA4, NDUFA4L2, NDUFA5, NDUFA6, NDUFA7, NDUFA8, NDUFA9,NDUFAB1, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFAF7,NDUFAF8, NDUFB1, NDUFB10, NDUFB11, NDUFB2, NDUFB3, NDUFB4, NDUFB5,NDUFB6, NDUFB7, NDUFB8, NDUFB9, NDUFC1, NDUFC2, NDUFC2-KCTD14, NDUFS1,NDUFS2, NDUFS3, NDUFS4, NDUFS5, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2,NDUFV3, NEB, NEBL, NECABI, NECAB2, NECAB3, NECAPI, NECAP2, NECTINI,NECTIN2, NECTIN3, NECTIN4, NEDD1, NEDD4, NEDD4L, NEDD8, NEDD8-MDP1,NEDD9, NEFH, NEFL, NEFM, NEGR1, NEILI, NEIL2, NEIL3, NEK1, NEK10, NEK11,NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK8, NEK9, NELFA, NELFB, NELFCD,NELFE, NELL1, NELL2, NEMF, NEMP1, NEMP2, NENF, NEO1, NEPRO, NES, NET1,NETO1, NETO2, NEU1, NEU2, NEU3, NEU4, NEURL1, NEURL1B, NEURL2, NEURL3,NEURL4, NEURODI, NEUROD2, NEUROD4, NEUROD6, NEUROGI, NEUROG2, NEUROG3,NEXMIF, NEXN, NF1, NF2, NFAM1, NFASC, NFAT5, NFATC1, NFATC2, NFATC2IP,NFATC3, NFATC4, NFE2, NFE2L1, NFE2L2, NFE2L3, NFE4, NFIA, NFIB, NFIC,NFIL3, NFIX, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBID, NFKBIE, NFKBIL1,NFKBIZ, NFRKB, NFS1, NFU1, NFX1, NFXL1, NFYA, NFYB, NFYC, NGB, NGDN,NGEF, NGF, NGFR, NGLY1, NGRN, NHEJ1, NHLH1, NHLH2, NHLRC1, NHLRC2,NHLRC3, NHLRC4, NHP2, NHS, NHSL1, NHSL2, NICN1, NID1, NID2, NIF3L1,NIFK, NIM1K, NIN, NINJ1, NINJ2, NINL, NIP7, NIPA1, NIPA2, NIPAL1,NIPAL2, NIPAL3, NIPAL4, NIPBL, NIPSNAP1, NIPSNAP2, NIPSNAP3A, NIPSNAP3B,NISCH, NIT1, NIT2, NKAINI, NKAIN2, NKAIN3, NKAIN4, NKAP, NKAPL, NKD1,NKD2, NKG7, NKIRAS1, NKIRAS2, NKPD1, NKRF, NKTR, NKX1-1, NKX1-2, NKX2-1,NKX2-2, NKX2-3, NKX2-4, NKX2-5, NKX2-6, NKX2-8, NKX3-1, NKX3-2, NKX6-1,NKX6-2, NKX6-3, NLE1, NLGN1, NLGN2, NLGN3, NLGN4X, NLGN4Y, NLK, NLN,NLRC3, NLRC4, NLRC5, NLRP1, NLRP10, NLRP11, NLRP12, NLRP13, NLRP14,NLRP2, NLRP2B, NLRP3, NLRP4, NLRP5, NLRP6, NLRP7, NLRP8, NLRP9, NLRX1,NMB, NMBR, NMD3, NME1, NME1-NME2, NME2, NME3, NME4, NME5, NME6, NME7,NME8, NME9, NMI, NMNAT1, NMNAT2, NMNAT3, NMRAL1, NMRK1, NMRK2, NMS,NMT1, NMT2, NMU, NMUR1, NMUR2, NNAT, NNMT, NNT, NOA1, NOB1, NOBOX,NOC2L, NOC3L, NOC4L, NOCT, NOD1, NOD2, NODAL, NOG, NOL10, NOL11, NOL12,NOL3, NOL4, NOL4L, NOL6, NOL7, NOL8, NOL9, NOLC1, NOM1, NOMO1, NOMO2,NOMO3, NONO, NOP10, NOP14, NOP16, NOP2, NOP53, NOP56, NOP58, NOP9, NOS1,NOS1AP, NOS2, NOS3, NOSIP, NOSTRIN, NOTCHI, NOTCH2, NOTCH2NL, NOTCH3,NOTCH4, NOTO, NOTUM, NOV, NOVAl, NOVA2, NOX1, NOX3, NOX4, NOX5, NOXA1,NOXO1, NOXRED1, NPAP1, NPAS1, NPAS2, NPAS3, NPAS4, NPAT, NPB, NPBWR1,NPBWR2, NPC1, NPC1L1, NPC2, NPDC1, NPEPL1, NPEPPS, NPFF, NPFFR1, NPFFR2,NPHP1, NPHP3, NPHP3-ACAD11, NPHP4, NPHS1, NPHS2, NPIPA1, NPIPA2, NPIPA3,NPIPA5, NPIPA7, NPIPA8, NPIPB11, NPIPB12, NPIPB13, NPIPB15, NPIPB2,NPIPB3, NPIPB4, NPIPB5, NPIPB6, NPIPB7, NPIPB8, NPIPB9, NPL, NPLOC4,NPM1, NPM2, NPM3, NPNT, NPPA, NPPB, NPPC, NPR1, NPR2, NPR3, NPRL2,NPRL3, NPS, NPSR1, NPTN, NPTX1, NPTX2, NPTXR, NPVF, NPW, NPY, NPY1R,NPY2R, NPY4R, NPY4R2, NPY5R, NQO1, NQO2, NROB1, NROB2, NR1D1, NR1D2,NR1H2, NR1H3, NR1H4, NR1I2, NR1I3, NR2C1, NR2C2, NR2C2AP, NR2E1, NR2E3,NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2,NR6A1, NRAP, NRARP, NRAS, NRBF2, NRBP1, NRBP2, NRCAM, NRDC, NRDE2, NREP,NRF1, NRG1, NRG2, NRG3, NRG4, NRGN, NRIP1, NRIP2, NRIP3, NRK, NRL, NRM,NRN1, NRN1L, NRP1, NRP2, NRROS, NRSN1, NRSN2, NRTN, NRXN1, NRXN2, NRXN3,NSA2, NSD1, NSD2, NSD3, NSDHL, NSF, NSFL 1C, NSL 1, NSMAF, NSMCEl,NSMCE2, NSMCE3, NSMCE4A, NSMF, NSRP1, NSUN2, NSUN3, NSUN4, NSUN5, NSUN6,NSUN7, NT5C, NT5C1A, NT5C1B, NT5C1B-RDH14, NT5C2, NT5C3A, NT5C3B,NT5DC1, NT5DC2, NT5DC3, NT5DC4, NT5E, NT5M, NTAN1, NTF3, NTF4, NTHL1,NTM, NTMT1, NTN1, NTN3, NTN4, NTN5, NTNG1, NTNG2, NTPCR, NTRK1, NTRK2,NTRK3, NTS, NTSR1, NTSR2, NUAK1, NUAK2, NUB1, NUBP1, NUBP2, NUBPL,NUCB1, NUCB2, NUCKS1, NUDC, NUDCD1, NUDCD2, NUDCD3, NUDT1, NUDT10,NUDT11, NUDT12, NUDT13, NUDT14, NUDT15, NUDT16, NUDT16L1, NUDT17,NUDT18, NUDT19, NUDT2, NUDT21, NUDT22, NUDT3, NUDT4, NUDT4P1, NUDT5,NUDT6, NUDT7, NUDT8, NUDT9, NUF2, NUFIPI, NUFIP2, NUGGC, NUMA1, NUMB,NUMBL, NUP107, NUP133, NUP153, NUP155, NUP160, NUP188, NUP205, NUP210,NUP210L, NUP214, NUP35, NUP37, NUP43, NUP50, NUP54, NUP58, NUP62,NUP62CL, NUP85, NUP88, NUP93, NUP98, NUPL2, NUPR1, NUPR2, NUS1, NUSAP1,NUTF2, NUTM1, NUTM2A, NUTM2B, NUTM2D, NUTM2E, NUTM2F, NUTM2G, NVL, NWD1,NWD2, NXF1, NXF2, NXF2B, NXF3, NXF5, NXN, NXNL1, NXNL2, NXPE1, NXPE2,NXPE3, NXPE4, NXPH1, NXPH2, NXPH3, NXPH4, NXT1, NXT2, NYAP1, NYAP2,NYNRIN, NYX, OAF, OARD1, OAS1, OAS2, OAS3, OASL, OAT, OAZ1, OAZ2, OAZ3,OBP2A, OBP2B, OBSCN, OBSCN-AS1, OBSL1, OC90, OCA2, OCEL1, OCIAD1,OCIAD2, OCLM, OCLN, OCM, OCM2, OCRL, OCSTAMP, ODAM, ODC1, ODF1, ODF2,ODF2L, ODF3, ODF3B, ODF3L1, ODF3L2, ODF4, OFCC1, OFD1, OGDH, OGDHL,OGFOD1, OGFOD2, OGFOD3, OGFR, OGFRL1, OGG1, OGN, OGT, OIP5, OIT3, OLA1,OLAH, OLFM1, OLFM2, OLFM3, OLFM4, OLFML1, OLFML2A, OLFML2B, OLFML3,OLIG1, OLIG2, OLIG3, OLR1, OMA1, OMD, OMG, OMP, ONECUTI, ONECUT2,ONECUT3, OOEP, OOSP2, OPAl, OPA3, OPALIN, OPCML, OPHN1, OPLAH, OPN1LW,OPN1MW, OPN1MW2, OPN1MW3, OPN1SW, OPN3, OPN4, OPN5, OPRD1, OPRK1, OPRL1,OPRM1, OPRPN, OPTC, OPTN, OR10A2, OR10A3, OR10A4, OR10A5, OR10A6,OR10A7, OR10AC1, OR10AD1, OR10AG1, OR10C1, OR10D3, OR10G2, OR10G3,OR10G4, OR10G6, OR10G7, OR10G8, OR10G9, OR10H1, OR10H2, OR10H3, OR10H4,OR10H5, OR10J1, OR10J3, OR10J4, OR10J5, OR10K1, OR10K2, OR10P1, OR10Q1,OR10R2, OR10S1, OR10T2, OR10V1, OR10W1, OR10X1, OR10Z1, OR11A1, OR11G2,OR11H1, OR11H12, OR11H2, OR11H4, OR11H6, OR11H7, OR11L1, OR12D1, OR12D2,OR12D3, OR13A1, OR13C2, OR13C3, OR13C4, OR13C5, OR13C7, OR13C8, OR13C9,OR13D1, OR13F1, OR13G1, OR13H1, OR13J1, OR14A16, OR14A2, OR14C36,OR14I1, OR14J1, OR14K1, OR1A1, OR1A2, OR1B1, OR1C1, OR1D2, OR1D5, OR1E1,OR1E2, OR1F1, OR1G1, OR1I1, OR1J1, OR1J2, OR1J4, OR1K1, OR1L1, OR1L3,OR1L4, OR1L6, OR1L8, OR1M1, OR1N1, OR1N2, OR1P1, OR1Q1, OR1S1, OR1S2,OR2A1, OR2A12, OR2A14, OR2A2, OR2A25, OR2A4, OR2A42, OR2A5, OR2A7,OR2AE1, OR2AG1, OR2AG2, OR2AJ1, OR2AK2, OR2AP1, OR2AT4, OR2B11, OR2B2,OR2B3, OR2B6, OR2C1, OR2C3, OR2D2, OR2D3, OR2F1, OR2F2, OR2G2, OR2G3,OR2G6, OR2H1, OR2H2, OR2J1, OR2J2, OR2J3, OR2K2, OR2L13, OR2L2, OR2L3,OR2L5, OR2L8, OR2M2, OR2M3, OR2M4, OR2M5, OR2M7, OR2S2, OR2T1, OR2T10,OR2T11, OR2T12, OR2T2, OR2T27, OR2T29, OR2T3, OR2T33, OR2T34, OR2T35,OR2T4, OR2T5, OR2T6, OR2T7, OR2T8, OR2V1, OR2V2, OR2W1, OR2W3, OR2Y1,OR2Z1, OR3A1, OR3A2, OR3A3, OR4A15, OR4A16, OR4A47, OR4A5, OR4A8, OR4B1,OR4C11, OR4C12, OR4C13, OR4C15, OR4C16, OR4C3, OR4C45, OR4C46, OR4C5,OR4C6, OR4D1, OR4D10, OR4D11, OR4D2, OR4D5, OR4D6, OR4D9, OR4E1, OR4E2,OR4F15, OR4F16, OR4F17, OR4F21, OR4F29, OR4F3, OR4F4, OR4F5, OR4F6,OR4K1, OR4K13, OR4K14, OR4K15, OR4K17, OR4K2, OR4K3, OR4K5, OR4L1,OR4M1, OR4M2, OR4N2, OR4N4, OR4N5, OR4P4, OR4Q2, OR4Q3, OR4S1, OR4S2,OR4X1, OR4X2, OR51A2, OR51A4, OR51A7, OR51B2, OR51B4, OR51B5, OR51B6,OR51D1, OR51E1, OR51E2, OR51F1, OR51F2, OR51G1, OR51G2, OR51H1, OR51I1,OR51I2, OR51J1, OR51L1, OR51M1, OR51Q1, OR51S1, OR51T1, OR51V1, OR52A1,OR52A5, OR52B2, OR52B4, OR52B6, OR52D1, OR52E2, OR52E4, OR52E5, OR52E6,OR52E8, OR52H1, OR52I1, OR52I2, OR52J3, OR52K1, OR52K2, OR52L1, OR52M1,OR52N1, OR52N2, OR52N4, OR52N5, OR52R1, OR52W1, OR52Z1, OR56A1, OR56A3,OR56A4, OR56A5, OR56B1, OR56B4, OR5A1, OR5A2, OR5AC1, OR5AC2, OR5AK2,OR5AN1, OR5AP2, OR5AR1, OR5AS1, OR5AU1, OR5B12, OR5B17, OR5B2, OR5B21,OR5B3, OR5C1, OR5D13, OR5D14, OR5D16, OR5D18, OR5F1, OR5G3, OR5H1,OR5H14, OR5H15, OR5H2, OR5H6, OR5H8, OR5I1, OR5J2, OR5K1, OR5K2, OR5K3,OR5K4, OR5L1, OR5L2, OR5M1, OR5M10, OR5M11, OR5M3, OR5M8, OR5M9, OR5P2,OR5P3, OR5R1, OR5T1, OR5T2, OR5T3, OR5V1, OR5W2, OR6A2, OR6B1, OR6B2,OR6B3, OR6C1, OR6C2, OR6C3, OR6C4, OR6C6, OR6C65, OR6C68, OR6C70,OR6C74, OR6C75, OR6C76, OR6F1, OR6J1, OR6K2, OR6K3, OR6K6, OR6M1, OR6N1,OR6N2, OR6P1, OR6Q1, OR6S1, OR6T1, OR6V1, OR6X1, OR6Y1, OR7A10, OR7A17,OR7A5, OR7C1, OR7C2, OR7D2, OR7D4, OR7E24, OR7G1, OR7G2, OR7G3, OR8A1,OR8B12, OR8B2, OR8B3, OR8B4, OR8B8, OR8D1, OR8D2, OR8D4, OR8G1, OR8G5,OR8H1, OR8H2, OR8H3, OR8I2, OR8J1, OR8J2, OR8J3, OR8K1, OR8K3, OR8K5,OR8S1, OR8U1, OR8U8, OR9A2, OR9A4, OR9G1, OR9G4, OR9G9, OR9H1P, OR9I1,OR9K2, OR9Q1, OR9Q2, ORAIl, ORAI2, ORAI3, ORAOV1, ORC1, ORC2, ORC3,ORC4, ORC5, ORC6, ORM1, ORM2, ORMDL1, ORMDL2, ORMDL3, OS9, OSBP, OSBP2,OSBPL10, OSBPL11, OSBPL1A, OSBPL2, OSBPL3, OSBPL5, OSBPL6, OSBPL7,OSBPL8, OSBPL9, OSCAR, OSCP1, OSER1, OSGEP, OSGEPLI, OSGINI, OSGIN2,OSM, OSMR, OSR1, OSR2, OST4, OSTC, OSTF1, OSTM1, OSTN, OTC, OTOA, OTOF,OTOG, OTOGL, OTOL1, OTOP1, OTOP2, OTOP3, OTOR, OTOS, OTP, OTUB1, OTUB2,OTUD1, OTUD3, OTUD4, OTUD5, OTUD6A, OTUD6B, OTUD7A, OTUD7B, OTULIN,OTX1, OTX2, OVCA2, OVCH1, OVCH2, OVGP1, OVOL1, OVOL2, OVOL3, OXA1L,OXCT1, OXCT2, OXER1, OXGR1, OXLD1, OXNAD1, OXR1, OXSM, OXSR1, OXT, OXTR,P2RX1, P2RX2, P2RX3, P2RX4, P2RX5, P2RX5-TAX1BP3, P2RX6, P2RX7, P2RYl,P2RY10, P2RY11, P2RYl2, P2RY13, P2RYl4, P2RY2, P2RY4, P2RY6, P2RY8,P3H1, P3H2, P3H3, P3H4, P4HA1, P4HA2, P4HA3, P4HB, P4HTM, PA2G4, PAAF1,PABPC1, PABPC1L, PABPC1L2A, PABPC1L2B, PABPC3, PABPC4, PABPC4L, PABPC5,PABPN1, PABPN1L, PACRG, PACRGL, PACS1, PACS2, PACSIN1, PACSIN2, PACSIN3,PADI1, PADI2, PADI3, PADI4, PADI6, PAEP, PAF1, PAFAHIB1, PAFAH1B2,PAFAH1B3, PAFAH2, PAG1, PAGEl, PAGE2, PAGE2B, PAGE3, PAGE4, PAGE5,PAGR1, PAH, PAICS, PAIP1, PAIP2, PAIP2B, PAK1, PAK1IP1, PAK2, PAK3,PAK4, PAK5, PAK6, PALB2, PALD1, PALLD, PALM, PALM2, PALM2-AKAP2, PALM3,PALMD, PAM, PAM16, PAMR1, PAN2, PAN3, PANK1, PANK2, PANK3, PANK4, PANO1,PANX1, PANX2, PANX3, PAOX, PAPD4, PAPD5, PAPD7, PAPLN, PAPOLA, PAPOLB,PAPOLG, PAPPA, PAPPA2, PAPSS1, PAPSS2, PAQR3, PAQR4, PAQR5, PAQR6,PAQR7, PAQR8, PAQR9, PARD3, PARD3B, PARD6A, PARD6B, PARD6G, PARG, PARK7,PARL, PARM1, PARN, PARP1, PARP10, PARP11, PARP12, PARP14, PARP15,PARP16, PARP2, PARP3, PARP4, PARP6, PARP8, PARP9, PARPBP, PARS2, PARVA,PARVB, PARVG, PASD1, PASK, PATE1, PATE2, PATE3, PATE4, PATJ, PATL1,PATL2, PATZ1, PAWR, PAX1, PAX2, PAX3, PAX4, PAX5, PAX6, PAX7, PAX8,PAX9, PAXBP1, PAXIP1, PAXX, PBDC1, PBK, PBLD, PBOV1, PBRM1, PBX1, PBX2,PBX3, PBX4, PBXIP1, PC, PCBD1, PCBD2, PCBP1, PCBP2, PCBP3, PCBP4, PCCA,PCCB, PCDH1, PCDH10, PCDH11X, PCDH11Y, PCDH12, PCDH15, PCDH17, PCDH18,PCDH19, PCDH20, PCDH7, PCDH8, PCDH9, PCDHA1, PCDHA10, PCDHA11, PCDHA12,PCDHA13, PCDHA2, PCDHA3, PCDHA4, PCDHA5, PCDHA6, PCDHA7, PCDHA8, PCDHA9,PCDHAC1, PCDHAC2, PCDHB1, PCDHB10, PCDHB11, PCDHB12, PCDHB13, PCDHB14,PCDHB15, PCDHB16, PCDHB2, PCDHB3, PCDHB4, PCDHB5, PCDHB6, PCDHB7,PCDHB8, PCDHB9, PCDHGA1, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGA2, PCDHGA3,PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGB1, PCDHGB2,PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB6, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5,PCED1A, PCED1B, PCF11, PCGF1, PCGF2, PCGF3, PCGF5, PCGF6, PCID2, PCIF1,PCK1, PCK2, PCLAF, PCLO, PCM1, PCMT1, PCMTD1, PCMTD2, PCNA, PCNP, PCNT,PCNX1, PCNX2, PCNX3, PCNX4, PCOLCE, PCOLCE2, PCOTH, PCP2, PCP4, PCP4L1,PCSK1, PCSKlN, PCSK2, PCSK4, PCSK5, PCSK6, PCSK7, PCSK9, PCTP, PCYOX1,PCYOX1L, PCYT1A, PCYT1B, PCYT2, PDAP1, PDC, PDCD1, PDCD10, PDCD11,PDCD1LG2, PDCD2, PDCD2L, PDCD4, PDCD5, PDCD6, PDCD6IP, PDCD7, PDCL,PDCL2, PDCL3, PDE10A, PDE11A, PDE12, PDE1A, PDE1B, PDE1C, PDE2A, PDE3A,PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE4DIP, PDE5A, PDE6A, PDE6B, PDE6C,PDE6D, PDE6G, PDE6H, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, PDF, PDGFA,PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, PDGFRL, PDHA1, PDHA2, PDHB, PDHX,PDIA2, PDIA3, PDIA4, PDIA5, PDIA6, PDIK1L, PDILT, PDK1, PDK2, PDK3,PDK4, PDL1M1, PDL1M2, PDL1M3, PDL1M4, PDL1M5, PDL1M7, PDP1, PDP2, PDPK1,PDPN, PDPR, PDRG1, PDS5A, PDS5B, PDSS1, PDSS2, PDX1, PDXDC1, PDXK, PDXP,PDYN, PDZD11, PDZD2, PDZD3, PDZD4, PDZD7, PDZD8, PDZD9, PDZK1, PDZK1IP1,PDZRN3, PDZRN4, PEA15, PEAK1, PEAR1, PEBP1, PEBP4, PECAM1, PECR, PEF1,PEG10, PEG3, PELI1, PELI2, PELI3, PELO, PELP1, PEMT, PENK, PEPD, PER1,PER2, PER3, PERM1, PERP, PES1, PET100, PET 117, PEX1, PEX10, PEX11A,PEX11B, PEX11G, PEX12, PEX13, PEX14, PEX16, PEX19, PEX2, PEX26, PEX3,PEX5, PEX5L, PEX6, PEX7, PF4, PF4V1, PFAS, PFDN1, PFDN2, PFDN4, PFDN5,PFDN6, PFKFB1, PFKFB2, PFKFB3, PFKFB4, PFKL, PFKM, PFKP, PFN1, PFN2,PFN3, PFN4, PGA3, PGA4, PGA5, PGAM1, PGAM2, PGAM4, PGAM5, PGAP1, PGAP2,PGAP3, PGBD1, PGBD2, PGBD4, PGBD5, PGC, PGD, PGF, PGGHG, PGGTIB, PGK1,PGK2, PGLS, PGLYRP1, PGLYRP2, PGLYRP3, PGLYRP4, PGM1, PGM2, PGM2L1,PGM3, PGM5, PGP, PGPEP1, PGPEP1L, PGR, PGRMC1, PGRMC2, PGS1, PHACTRI,PHACTR2, PHACTR3, PHACTR4, PHAX, PHB, PHB2, PHC1, PHC2, PHC3, PHEX,PHF1, PHF10, PHF11, PHF12, PHF13, PHF14, PHF19, PHF2, PHF20, PHF20L1,PHF21A, PHF21B, PHF23, PHF24, PHF3, PHF5A, PHF6, PHF7, PHF8, PHGDH,PHGR1, PHIP, PHKA1, PHKA2, PHKB, PHKG1, PHKG2, PHLDA1, PHLDA2, PHLDA3,PHLDB1, PHLDB2, PHLDB3, PHLPP1, PHLPP2, PHOSPHO1, PHOSPHO2, PHOX2A,PHOX2B, PHPT1, PHRF1, PHTF1, PHTF2, PHYH, PHYHD1, PHYHIP, PHYHIPL,PHYKPL, PI15, PI16, PI3, PI4K2A, PI4K2B, PI4KA, PI4 KB, PIANP, PIAS1,PIAS2, PIAS3, PIAS4, PIBF1, PICALM, PICK1, PID1, PIDD1, PIEZO1, PIEZO2,PIF1, PIFO, PIGA, PIGB, PIGBOS1, PIGC, PIGF, PIGG, PIGH, PIGK, PIGL,PIGM, PIGN, PIGO, PIGP, PIGQ, PIGR, PIGS, PIGT, PIGU, PIGV, PIGW, PIGX,PIGY, PIGZ, PIH1D1, PIH1D2, PIH1D3, PIK3AP1, PIK3C2A, PIK3C2B, PIK3C2G,PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3,PIK3R4, PIK3R5, PIK3R6, PIKFYVE, PILRA, PILRB, PIM1, PIM2, PIM3, PIMREG,PIN1, PIN4, PINK1, PINLYP, PINX1, PIP, PIP4K2A, PIP4K2B, PIP4K2C,PIP5K1A, PIP5K1B, PIP5K1C, PIP5KL1, PIPOX, PIR, PIRT, PISD, PITHD1,PITPNA, PITPNB, PITPNC1, PITPNM1, PITPNM2, PITPNM3, PITRM1, PITX1,PITX2, PITX3, PIWIL1, PIWIL2, PIWIL3, PIWIL4, PJA1, PJA2, PKD1, PKD1L1,PKD1L2, PKD1L3, PKD2, PKD2L1, PKD2L2, PKDCC, PKDREJ, PKHD1, PKHDILl,PKIA, PKIB, PKIG, PKLR, PKM, PKMYT1, PKN1, PKN2, PKN3, PKNOX1, PKNOX2,PKP1, PKP2, PKP3, PKP4, PLA1A, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15,PLA2G16, PLA2G1B, PLA2G2A, PLA2G2C, PLA2G2D, PLA2G2E, PLA2G2F, PLA2G3,PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F, PLA2G5, PLA2G6,PLA2G7, PLA2R1, PLAA, PLAC1, PLAC4, PLAC8, PLAC8L1, PLAC9, PLAG1,PLAGLI, PLAGL2, PLAT, PLAU, PLAUR, PLB1, PLBD1, PLBD2, PLCB1, PLCB2,PLCB3, PLCB4, PLCD1, PLCD3, PLCD4, PLCE1, PLCG1, PLCG2, PLCH1, PLCH2,PLCL1, PLCL2, PLCXD1, PLCXD2, PLCXD3, PLCZ1, PLD1, PLD2, PLD3, PLD4,PLD5, PLD6, PLEC, PLEK, PLEK2, PLEKHA1, PLEKHA2, PLEKHA3, PLEKHA4,PLEKHA5, PLEKHA6, PLEKHA7, PLEKHA8, PLEKHB1, PLEKHB2, PLEKHD1, PLEKHF1,PLEKHF2, PLEKHG1, PLEKHG2, PLEKHG3, PLEKHG4, PLEKHG4B, PLEKHG5, PLEKHG6,PLEKHG7, PLEKHHI, PLEKHH2, PLEKHH3, PLEKHJ1, PLEKHMI, PLEKHM2, PLEKHM3,PLEKHN1, PLEKHO1, PLEKHO2, PLEKHS1, PLET1, PLG, PLGLB1, PLGLB2, PLGRKT,PLIN1, PLIN2, PLIN3, PLIN4, PLIN5, PLK1, PLK2, PLK3, PLK4, PLK5, PLLP,PLN, PLOD1, PLOD2, PLOD3, PLP1, PLP2, PLPBP, PLPP1, PLPP2, PLPP3, PLPP4,PLPP5, PLPP6, PLPP7, PLPPR1, PLPPR2, PLPPR3, PLPPR4, PLPPR5, PLRG1,PLS1, PLS3, PLSCR1, PLSCR2, PLSCR3, PLSCR4, PLSCR5, PLTP, PLVAP, PLXDC1,PLXDC2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, PLXNB1, PLXNB2, PLXNB3, PLXNC1,PLXND1, PM20D1, PM20D2, PMAIP1, PMCH, PMEL, PMEPA1, PMF1, PMF1-BGLAP,PMFBP1, PML, PMM1, PMM2, PMP2, PMP22, PMPCA, PMPCB, PMS1, PMS2, PMVK,PNCK, PNISR, PNKD, PNKP, PNLDC1, PNLIP, PNLIPRP1, PNLIPRP2, PNLIPRP3,PNMA1, PNMA2, PNMA3, PNMA5, PNMA6A, PNMA6E, PNMA6F, PNMA8A, PNMA8B,PNMA8C, PNMT, PNN, PNO1, PNOC, PNP, PNPLA1, PNPLA2, PNPLA3, PNPLA4,PNPLA5, PNPLA6, PNPLA7, PNPLA8, PNPO, PNPT1, PNRC1, PNRC2, POC1A, POC1B,POC1B-GALNT4, POC5, PODN, PODNL1, PODXL, PODXL2, POF1B, POFUT1, POFUT2,POGK, POGLUT1, POGZ, POLA1, POLA2, POLB, POLD1, POLD2, POLD3, POLD4,POLDIP2, POLDIP3, POLE, POLE2, POLE3, POLE4, POLG, POLG2, POLH, POLI,POLK, POLL, POLM, POLN, POLQ, POLR1A, POLR1B, POLR1C, POLR1D, POLR1E,POLR2A, POLR2B, POLR2C, POLR2D, POLR2E, POLR2F, POLR2G, POLR2H, POLR2I,POLR2J, POLR2J2, POLR2J3, POLR2K, POLR2L, POLR2M, POLR3A, POLR3B,POLR3C, POLR3D, POLR3E, POLR3F, POLR3G, POLR3GL, POLR3H, POLR3K, POLRMT,POM121, POM121C, POM121L12, POM121L2, POMC, POMGNT1, POMGNT2, POMK,POMP, POMT1, POMT2, POMZP3, PON1, PON2, PON3, POP1, POP4, POP5, POP7,POPDC2, POPDC3, POR, PORCN, POSTN, POT1, POTEA, POTEB, POTEB2, POTEB3,POTEC, POTED, POTEE, POTEF, POTEG, POTEH, POTEI, POTEJ, POTEM, POU1F1,POU2AF1, POU2F1, POU2F2, POU2F3, POU3F1, POU3F2, POU3F3, POU3F4, POU4F1,POU4F2, POU4F3, POU5F1, POU5F1B, POU5F2, POU6F1, POU6F2, PP2D1, PPA1,PPA2, PPAN, PPAN-P2RY11, PPARA, PPARD, PPARG, PPARGC1A, PPARGCIB, PPAT,PPBP, PPCDC, PPCS, PPDPF, PPEF1, PPEF2, PPFIA1, PPFIA2, PPFIA3, PPFIA4,PPFIBP1, PPFIBP2, PPHLN1, PPIA, PPIAL4A, PPIAL4C, PPIAL4D, PPIAL4E,PPIAL4F, PPIAL4G, PPIB, PPIC, PPID, PPIE, PPIF, PPIG, PPIH, PPIL1,PPIL2, PPIL3, PPIL4, PPIL6, PPIP5K1, PPIP5K2, PPL, PPM1A, PPM1B, PPM1D,PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M, PPM1N, PPMEl,PPOX, PPP1CA, PPP1CB, PPP1CC, PPP1R10, PPP1R11, PPP1R12A, PPP1R12B,PPP1R12C, PPP1R13B, PPP1R13L, PPP1R14A, PPP1R14B, PPP1R14C, PPP1R14D,PPP1R15A, PPP1R15B, PPP1R16A, PPP1R16B, PPP1R17, PPP1R18, PPP1R1A,PPP1R1B, PPP1R1C, PPP1R2, PPP1R21, PPP1R26, PPP1R27, PPP1R2P3, PPP1R2P9,PPP1R32, PPP1R35, PPP1R36, PPP1R37, PPP1R3A, PPP1R3B, PPP1R3C, PPP1R3D,PPP1R3E, PPP1R3F, PPP1R3G, PPP1R42, PPP1R7, PPP1R8, PPP1R9A, PPP1R9B,PPP2CA, PPP2CB, PPP2R1A, PPP2R1B, PPP2R2A, PPP2R2B, PPP2R2C, PPP2R2D,PPP2R3A, PPP2R3B, PPP2R3C, PPP2R5A, PPP2R5B, PPP2R5C, PPP2R5D, PPP2R5E,PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PPP4C, PPP4R1, PPP4R2, PPP4R3A,PPP4R3B, PPP4R3CP, PPP4R4, PPP5C, PPP5D1, PPP6C, PPP6R1, PPP6R2, PPP6R3,PPRC1, PPT1, PPT2, PPT2-EGFL8, PPTC7, PPWD1, PPY, PQBP1, PQLC1, PQLC2,PQLC2L, PQLC3, PRACI, PRAC2, PRADC1, PRAF2, PRAGI, PRAM1, PRAME,PRAMEF1, PRAMEF10, PRAMEF11, PRAMEF12, PRAMEF13, PRAMEF14, PRAMEF15,PRAMEF17, PRAMEF18, PRAMEF19, PRAMEF2, PRAMEF20, PRAMEF25, PRAMEF26,PRAMEF27, PRAMEF33, PRAMEF4, PRAMEF5, PRAMEF6, PRAMEF7, PRAMEF8,PRAMEF9, PRAPI, PRB1, PRB2, PRB3, PRB4, PRC1, PRCC, PRCD, PRCP, PRDM1,PRDM10, PRDM11, PRDM12, PRDM13, PRDM14, PRDM15, PRDM16, PRDM2, PRDM4,PRDM5, PRDM6, PRDM7, PRDM8, PRDM9, PRDX1, PRDX2, PRDX3, PRDX4, PRDX5,PRDX6, PREB, PRELID1, PRELID2, PRELID3A, PRELID3B, PRELP, PREP, PREPL,PREXI, PREX2, PRF1, PRG2, PRG3, PRG4, PRH1, PRH2, PRICKLE1, PRICKLE2,PRICKLE3, PRICKLE4, PRIMI, PRIM2, PRIMAl, PRIMPOL, PRKAA1, PRKAA2,PRKAB1, PRKAB2, PRKACA, PRKACB, PRKACG, PRKAG1, PRKAG2, PRKAG3, PRKAR1A,PRKAR1B, PRKAR2A, PRKAR2B, PRKCA, PRKCB, PRKCD, PRKCE, PRKCG, PRKCH,PRKCI, PRKCQ, PRKCSH, PRKCZ, PRKD1, PRKD2, PRKD3, PRKDC, PRKG1, PRKG2,PRKN, PRKRA, PRKRIP1, PRKX, PRL, PRLH, PRLHR, PRLR, PRM1, PRM2, PRM3,PRMT1, PRMT2, PRMT3, PRMT5, PRMT6, PRMT7, PRMT8, PRMT9, PRND, PRNP,PRNT, PROB1, PROC, PROCA1, PROCR, PRODH, PRODH2, PROK1, PROK2, PROKR1,PROKR2, PROM1, PROM2, PROP1, PRORY, PROS1, PROSER1, PROSER2, PROSER3,PROXI, PROX2, PROZ, PRPF18, PRPF19, PRPF3, PRPF31, PRPF38A, PRPF38B,PRPF39, PRPF4, PRPF40A, PRPF40B, PRPF4B, PRPF6, PRPF8, PRPH, PRPH2,PRPS1, PRPS1L1, PRPS2, PRPSAP1, PRPSAP2, PRR11, PRR12, PRR13, PRR14,PRR14L, PRR15, PRR15L, PRR16, PRR18, PRR19, PRR20A, PRR20B, PRR20C,PRR20D, PRR20E, PRR21, PRR22, PRR23A, PRR23B, PRR23C, PRR23D1, PRR23D2,PRR25, PRR26, PRR27, PRR29, PRR3, PRR30, PRR32, PRR34, PRR35, PRR36,PRR4, PRR5, PRR5-ARHGAP8, PRR5L, PRR7, PRR9, PRRC1, PRRC2A, PRRC2B,PRRC2C, PRRG1, PRRG2, PRRG3, PRRG4, PRRT1, PRRT2, PRRT3, PRRT4, PRRX1,PRRX2, PRSS1, PRSS12, PRSS16, PRSS2, PRSS21, PRSS22, PRSS23, PRSS27,PRSS3, PRSS33, PRSS35, PRSS36, PRSS37, PRSS38, PRSS41, PRSS42, PRSS45,PRSS46, PRSS48, PRSS50, PRSS51, PRSS53, PRSS54, PRSS55, PRSS56, PRSS57,PRSS58, PRSS8, PRTFDC1, PRTG, PRTN3, PRUNE1, PRUNE2, PRX, PRY, PRY2,PSAP, PSAPLI, PSATI, PSCA, PSD, PSD2, PSD3, PSD4, PSENI, PSEN2, PSENEN,PSG1, PSG11, PSG2, PSG3, PSG4, PSG5, PSG6, PSG7, PSG8, PSG9, PSIP1,PSKH1, PSKH2, PSMA1, PSMA2, PSMA3, PSMA4, PSMA5, PSMA6, PSMA7, PSMA8,PSMB1, PSMB10, PSMB11, PSMB2, PSMB3, PSMB4, PSMB5, PSMB6, PSMB7, PSMB8,PSMB9, PSMC1, PSMC2, PSMC3, PSMC3IP, PSMC4, PSMC5, PSMC6, PSMD1, PSMD10,PSMD11, PSMD12, PSMD13, PSMD14, PSMD2, PSMD3, PSMD4, PSMD5, PSMD6,PSMD7, PSMD8, PSMD9, PSMEl, PSME2, PSME3, PSME4, PSMF1, PSMG1, PSMG2,PSMG3, PSMG4, PSORSICI, PSORS1C2, PSPC1, PSPH, PSPN, PSRC1, PSTK,PSTPIP1, PSTPIP2, PTAFR, PTAR1, PTBP1, PTBP2, PTBP3, PTCD1, PTCD2,PTCD3, PTCH1, PTCH2, PTCHD1, PTCHD3, PTCHD4, PTCRA, PTDSS1, PTDSS2,PTEN, PTER, PTF1A, PTGDR, PTGDR2, PTGDS, PTGER1, PTGER2, PTGER3, PTGER4,PTGES, PTGES2, PTGES3, PTGES3L, PTGES3L-AARSD1, PTGFR, PTGFRN, PTGIR,PTGIS, PTGR1, PTGR2, PTGS1, PTGS2, PTH, PTH1R, PTH2, PTH2R, PTHLH, PTK2,PTK2B, PTK6, PTK7, PTMA, PTMS, PTN, PTOV1, PTP4A1, PTP4A2, PTP4A3, PTPA,PTPDC1, PTPMT1, PTPN1, PTPN11, PTPN12, PTPN13, PTPN14, PTPN18, PTPN2,PTPN20, PTPN21, PTPN22, PTPN23, PTPN3, PTPN4, PTPN5, PTPN6, PTPN7,PTPN9, PTPRA, PTPRB, PTPRC, PTPRCAP, PTPRD, PTPRE, PTPRF, PTPRG, PTPRH,PTPRJ, PTPRK, PTPRM, PTPRN, PTPRN2, PTPRO, PTPRQ, PTPRR, PTPRS, PTPRT,PTPRU, PTPRZl, PTRH1, PTRH2, PTRHD1, PTS, PTTG1, PTTG1IP, PTTG2, PTX3,PTX4, PUDP, PUF60, PUMI, PUM2, PUM3, PURA, PURB, PURG, PUSI, PUS10,PUS3, PUS7, PUS7L, PUSL1, PVALB, PVR, PVRIG, PWP1, PWP2, PWWP2A, PWWP2B,PXDC1, PXDN, PXDNL, PXK, PXMP2, PXMP4, PXN, PXT1, PXYLP1, PYCARD, PYCR1,PYCR2, PYCR3, PYDC1, PYDC2, PYGB, PYGL, PYGM, PYGO1, PYGO2, PYHIN1,PYM1, PYROXD1, PYROXD2, PYURF, PYY, PZP, QARS, QDPR, QKI, QPCT, QPCTL,QPRT, QRFP, QRFPR, QRICH1, QRICH2, QRSL1, QSER1, QSOX1, QSOX2, QTRT1,QTRT2, R3HCC1, R3HCC1L, R3HDM1, R3HDM2, R3HDM4, R3HDML, RAB10, RAB11A,RAB11B, RAB11FIP1, RAB11FIP2, RAB11FIP3, RAB11FIP4, RAB11FIP5, RAB12,RAB13, RAB14, RAB15, RAB17, RAB18, RAB19, RAB1A, RAB1B, RAB20, RAB21,RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB29, RAB2A,RAB2B, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37,RAB38, RAB39A, RAB39B, RAB3A, RAB3B, RAB3C, RAB3D, RAB3GAP1, RAB3GAP2,RAB3IL1, RAB3IP, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, RAB43,RAB44, RAB4A, RAB4B, RAB4B-EGLN2, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B,RAB6C, RAB7A, RAB7B, RAB8A, RAB8B, RAB9A, RAB9B, RABACI, RABEPI, RABEP2,RABEPK, RABGAP1, RABGAP1L, RABGEF1, RABGGTA, RABGGTB, RABIF, RABL2A,RABL2B, RABL3, RABL6, RAC1, RAC2, RAC3, RACGAP1, RACK1, RAD1, RAD17,RAD18, RAD21, RAD21L1, RAD23A, RAD23B, RAD50, RAD51, RAD51AP1, RAD51AP2,RAD51B, RAD51C, RAD51D, RAD52, RAD54B, RAD54L, RAD54L2, RAD9A, RAD9B,RADIL, RAEl, RAETIE, RAETIG, RAETIL, RAF1, RAG1, RAG2, RAIl, RAI14,RAI2, RALA, RALB, RALBP1, RALGAPA1, RALGAPA2, RALGAPB, RALGDS, RALGPS1,RALGPS2, RALY, RALYL, RAMP1, RAMP2, RAMP3, RAN, RANBP1, RANBP10,RANBP17, RANBP2, RANBP3, RANBP3L, RANBP6, RANBP9, RANGAP1, RANGRF,RAPlA, RAP1B, RAP1GAP, RAP1GAP2, RAP1GDS1, RAP2A, RAP2B, RAP2C, RAPGEF1,RAPGEF2, RAPGEF3, RAPGEF4, RAPGEF5, RAPGEF6, RAPGEFL1, RAPH1, RAPSN,RARA, RARB, RARG, RARRESI, RARRES2, RARRES3, RARS, RARS2, RASA1, RASA2,RASA3, RASA4, RASA4B, RASAL1, RASAL2, RASAL3, RASD1, RASD2, RASEF,RASGEF1A, RASGEFIB, RASGEFIC, RASGRF1, RASGRF2, RASGRP1, RASGRP2,RASGRP3, RASGRP4, RASIP1, RASL10A, RASL10B, RASL11A, RASL11B, RASL12,RASSF1, RASSF10, RASSF2, RASSF3, RASSF4, RASSF5, RASSF6, RASSF7, RASSF8,RASSF9, RAVERI, RAVER2, RAX, RAX2, RB1, RB1CC1, RBAK, RBAK-RBAKDN,RBBP4, RBBP5, RBBP6, RBBP7, RBBP8, RBBP8NL, RBBP9, RBCK1, RBFA, RBFOX1,RBFOX2, RBFOX3, RBKS, RBL1, RBL2, RBM10, RBM11, RBM12, RBM12B, RBM14,RBM14-RBM4, RBM15, RBM15B, RBM17, RBM18, RBM19, RBM20, RBM22, RBM23,RBM24, RBM25, RBM26, RBM27, RBM28, RBM3, RBM33, RBM34, RBM38, RBM39,RBM4, RBM41, RBM42, RBM43, RBM44, RBM45, RBM46, RBM47, RBM48, RBM4B,RBM5, RBM6, RBM7, RBM8A, RBMS1, RBMS2, RBMS3, RBMX, RBMX2, RBMXL1,RBMXL2, RBMXL3, RBMYlA1, RBMYlB, RBMYlD, RBMY1E, RBMYlF, RBMYlJ, RBP1,RBP2, RBP3, RBP4, RBP5, RBP7, RBPJ, RBPJL, RBPMS, RBPMS2, RBSN, RBX1,RC3H1, RC3H2, RCAN1, RCAN2, RCAN3, RCBTB1, RCBTB2, RCC1, RCC1L, RCC2,RCCD1, RCE1, RCHY1, RCL1, RCN1, RCN2, RCN3, RCOR1, RCOR2, RCOR3, RCSD1,RCVRN, RD3, RD3L, RDH10, RDH11, RDH12, RDH13, RDH14, RDH16, RDH5, RDH8,RDM1, RDX, REC114, REC8, RECK, RECQL, RECQL4, RECQL5, REEP1, REEP2,REEP3, REEP4, REEP5, REEP6, REGlA, REG1B, REG3A, REG3G, REG4, REL, RELA,RELB, RELL1, RELL2, RELN, RELT, REM1, REM2, REN, RENBP, REP15, REPIN 1,REPS1, REPS2, RER1, RERE, RERG, RERGL, RESP18, REST, RET, RETN, RETNLB,RETREGI, RETREG2, RETREG3, RETSAT, REV1, REV3L, REXO1, REXO2, REXO4,REXO5, RFC1, RFC2, RFC3, RFC4, RFC5, RFESD, RFFL, RFK, RFLNA, RFLNB,RFNG, RFPL1, RFPL2, RFPL3, RFPL3S, RFPL4A, RFPL4AL1, RFPL4B, RFT1,RFTN1, RFTN2, RFWD2, RFWD3, RFX1, RFX2, RFX3, RFX4, RFX5, RFX6, RFX7,RFX8, RFXANK, RFXAP, RGCC, RGL1, RGL2, RGL3, RGL4, RGMA, RGMB, RGN,RGP1, RGPD1, RGPD2, RGPD3, RGPD4, RGPD5, RGPD6, RGPD8, RGR, RGS1, RGS10,RGS11, RGS12, RGS13, RGS14, RGS16, RGS17, RGS18, RGS19, RGS2, RGS20,RGS21, RGS22, RGS3, RGS4, RGS5, RGS6, RGS7, RGS7BP, RGS8, RGS9, RGS9BP,RGSL1, RHAG, RHBDD1, RHBDD2, RHBDD3, RHBDF1, RHBDF2, RHBDL1, RHBDL2,RHBDL3, RHBG, RHCE, RHCG, RHD, RHEB, RHEBLI, RHNO1, RHO, RHOA, RHOB,RHOBTB1, RHOBTB2, RHOBTB3, RHOC, RHOD, RHOF, RHOG, RHOH, RHOJ, RHOQ,RHOT1, RHOT2, RHOU, RHOV, RHOXF1, RHOXF2, RHOXF2B, RHPN1, RHPN2, RIBC1,RIBC2, RIC1, RIC3, RIC8A, RIC8B, RICTOR, RIDA, RIF1, RIIAD1, RILP,RILPL1, RILPL2, RIMBP2, RIMBP3, RIMBP3B, RIMBP3C, RIMKLA, RIMKLB, RIMS1,RIMS2, RIMS3, RIMS4, RIN1, RIN2, RIN3, RING1, RINL, RINT1, RIOK1, RIOK2,RIOK3, RIOX1, RIOX2, RIPK1, RIPK2, RIPK3, RIPK4, RIPOR1, RIPOR2, RIPOR3,RIPPLY1, RIPPLY2, RIPPLY3, RIT1, RIT2, RITA1, RLBP1, RLF, RLIM, RLN1,RLN2, RLN3, RMDN1, RMDN2, RMDN3, RMIl, RMI2, RMND1, RMND5A, RMND5B,RNASE1, RNASE10, RNASE11, RNASE12, RNASE13, RNASE2, RNASE3, RNASE4,RNASE6, RNASE7, RNASE8, RNASE9, RNASEH1, RNASEH2A, RNASEH2B, RNASEH2C,RNASEK, RNASEK-C17orf49, RNASEL, RNASET2, RND1, RND2, RND3, RNF10,RNF103, RNF103-CHMP3, RNF11, RNF111, RNF112, RNF113A, RNF113B, RNF114,RNF115, RNF121, RNF122, RNF123, RNF125, RNF126, RNF128, RNF13, RNF130,RNF133, RNF135, RNF138, RNF139, RNF14, RNF141, RNF144A, RNF144B, RNF145,RNF146, RNF148, RNF149, RNF150, RNF151, RNF152, RNF157, RNF165, RNF166,RNF167, RNF168, RNF169, RNF17, RNF170, RNF175, RNF180, RNF181, RNF182,RNF183, RNF185, RNF186, RNF187, RNF19A, RNF19B, RNF2, RNF20, RNF207,RNF208, RNF212, RNF212B, RNF213, RNF214, RNF215, RNF216, RNF217, RNF219,RNF220, RNF222, RNF223, RNF224, RNF225, RNF24, RNF25, RNF26, RNF31,RNF32, RNF34, RNF38, RNF39, RNF4, RNF40, RNF41, RNF43, RNF44, RNF5,RNF6, RNF7, RNF8, RNFT1, RNFT2, RNGTT, RNH1, RNLS, RNMT, RNPC3, RNPEP,RNPEPL1, RNPS1, ROBO1, ROBO2, ROBO3, ROBO4, ROCK1, ROCK2, ROGDI, ROM1,ROMO1, ROPN1, ROPN1B, ROPN1L, ROR1, ROR2, RORA, RORB, RORC, ROS1, RP1,RP1L1, RP2, RP9, RPA1, RPA2, RPA3, RPA4, RPAIN, RPAP1, RPAP2, RPAP3,RPE, RPE65, RPEL 1, RPF1, RPF2, RPGR, RPGRIP1, RPGRIP1L, RPH3A, RPH3AL,RPIA, RPL 10, RPL 10A, RPL10L, RPL11, RPL12, RPL13, RPL13A, RPL14,RPL15, RPL17, RPL17-C18orf32, RPL18, RPL18A, RPL19, RPL21, RPL22,RPL22L1, RPL23, RPL23A, RPL24, RPL26, RPL26L1, RPL27, RPL27A, RPL28,RPL29, RPL3, RPL30, RPL31, RPL32, RPL34, RPL35, RPL35A, RPL36, RPL36A,RPL36A-HNRNPH2, RPL36AL, RPL37, RPL37A, RPL38, RPL39, RPL39L, RPL3L,RPL4, RPL41, RPL5, RPL6, RPL7, RPL7A, RPL7L1, RPL8, RPL9, RPLPO, RPLP1,RPLP2, RPN1, RPN2, RPP14, RPP21, RPP25, RPP25L, RPP30, RPP38, RPP40,RPRD1A, RPRD1B, RPRD2, RPRM, RPRML, RPS10, RPS10-NUDT3, RPS11, RPS12,RPS13, RPS14, RPS15, RPS15A, RPS16, RPS17, RPS18, RPS19, RPS19BP1, RPS2,RPS20, RPS21, RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS27L, RPS28,RPS29, RPS3, RPS3A, RPS4X, RPS4Y1, RPS4Y2, RPS5, RPS6, RPS6KA1, RPS6KA2,RPS6KA3, RPS6KA4, RPS6KA5, RPS6KA6, RPS6KB1, RPS6KB2, RPS6KC1, RPS6KL1,RPS7, RPS8, RPS9, RPSA, RPTN, RPTOR, RPUSD1, RPUSD2, RPUSD3, RPUSD4,RRAD, RRAGA, RRAGB, RRAGC, RRAGD, RRAS, RRAS2, RRBP1, RREB1, RRH, RRM1,RRM2, RRM2B, RRN3, RRNAD1, RRP1, RRP12, RRP15, RRP1B, RRP36, RRP7A,RRP8, RRP9, RRS1, RS1, RSAD1, RSAD2, RSBN1, RSBN1L, RSC1A1, RSF1, RSG1,RSL1D1, RSL24D1, RSPH1, RSPH10B, RSPH10B2, RSPH14, RSPH3, RSPH4A,RSPH6A, RSPH9, RSPO1, RSPO2, RSPO3, RSPO4, RSPRYl, RSRC1, RSRC2, RSRP1,RSU1, RTBDN, RTCA, RTCB, RTEL1, RTEL1-TNFRSF6B, RTF1, RTFDC1, RTKN,RTKN2, RTL1, RTL10, RTL3, RTL4, RTL5, RTL6, RTL8A, RTL8B, RTL8C, RTL9,RTN1, RTN2, RTN3, RTN4, RTN4IP1, RTN4R, RTN4RL1, RTN4RL2, RTP1, RTP2,RTP3, RTP4, RTP5, RTTN, RUBCN, RUBCNL, RUFY1, RUFY2, RUFY3, RUFY4,RUNDC1, RUNDC3A, RUNDC3B, RUNX1, RUNX1T1, RUNX2, RUNX3, RUSC1, RUSC2,RUVBL1, RUVBL2, RWDD1, RWDD2A, RWDD2B, RWDD3, RWDD4, RXFP1, RXFP2,RXFP3, RXFP4, RXRA, RXRB, RXRG, RYBP, RYK, RYR1, RYR2, RYR3, S100A1,S100A10, S100A11, S100A12, S100A13, S100A14, S100A16, S100A2, S100A3,S100A4, S100A5, S100A6, S100A7, S100A7A, S100A7L2, S100A8, S100A9,S100B, S100G, S100P, S100PBP, S100Z, S1PR1, S1PR2, S1PR3, S1PR4, S1PR5,SAA1, SAA2, SAA2-SAA4, SAA4, SAAL1, SAC3D1, SACM1L, SACS, SAE1, SAFB,SAFB2, SAG, SAGE1, SALL1, SALL2, SALL3, SALL4, SAMD1, SAMD10, SAMD11,SAMD12, SAMD13, SAMD14, SAMD15, SAMD3, SAMD4A, SAMD4B, SAMD5, SAMD7,SAMD8, SAMD9, SAMD9L, SAMIHDI, SAMM50, SAMSN1, SAP130, SAP18, SAP25,SAP30, SAP30BP, SAP30L, SAPCD1, SAPCD2, SAR1A, SAR1B, SARAF, SARDH,SARM1, SARNP, SARS, SARS2, SART1, SART3, SASH1, SASH3, SASS6, SAT1,SAT2, SATB1, SATB2, SATL1, SAV1, SAXO1, SAXO2, SAYSD1, SBDS, SBF1, SBF2,SBK1, SBK2, SBK3, SBNO1, SBNO2, SBSN, SBSPON, SC5D, SCAF1, SCAF1I,SCAF4, SCAF8, SCAI, SCAMPI, SCAMP2, SCAMP3, SCAMP4, SCAMP5, SCANDI,SCAP, SCAPER, SCARA3, SCARA5, SCARB1, SCARB2, SCARF1, SCARF2, SCARTI,SCCPDH, SCD, SCD5, SCEL, SCFD1, SCFD2, SCG2, SCG3, SCG5, SCGBlA1,SCGB1C1, SCGB1C2, SCGB1D1, SCGB1D2, SCGB1D4, SCGB2A1, SCGB2A2, SCGB2B2,SCGB3A1, SCGB3A2, SCGN, SCHIP1, SCIMP, SCIN, SCLT1, SCLY, SCMH1, SCML1,SCML2, SCML4, SCN10A, SCN11A, SCN1A, SCN1B, SCN2A, SCN2B, SCN3A, SCN3B,SCN4A, SCN4B, SCN5A, SCN7A, SCN8A, SCN9A, SCNM1, SCNN1A, SCNN1B, SCNN1D,SCNN1G, SCO1, SC02, SCOC, SCP2, SCP2D1, SCPEP1, SCRG1, SCRIB, SCRN1,SCRN2, SCRN3, SCRT1, SCRT2, SCT, SCTR, SCUBEl, SCUBE2, SCUBE3, SCX,SCYL1, SCYL2, SCYL3, SDAD1, SDC1, SDC2, SDC3, SDC4, SDCBP, SDCBP2,SDCCAG3, SDCCAG8, SDE2, SDF2, SDF2L1, SDF4, SDHA, SDHAF1, SDHAF2,SDHAF3, SDHAF4, SDHB, SDHC, SDHD, SDK1, SDK2, SDR16C5, SDR39U1, SDR42E1,SDR42E2, SDR9C7, SDS, SDSL, SEBOX, SEC11A, SEC11C, SEC13, SEC14L1,SEC14L2, SEC14L3, SEC14L4, SEC14L5, SEC14L6, SEC16A, SEC16B, SEC22A,SEC22B, SEC22C, SEC23A, SEC23B, SEC23IP, SEC24A, SEC24B, SEC24C, SEC24D,SEC31A, SEC31B, SEC61A1, SEC61A2, SEC61B, SEC61G, SEC62, SEC63,SECISBP2, SECISBP2L, SECTM1, SEH1L, SEL1L, SEL1L2, SEL1L3, SELE,SELENBP1, SELENOF, SELENOH, SELENOI, SELENOK, SELENOM, SELENON, SELENOO,SELENOP, SELENOS, SELENOT, SELENOV, SELENOW, SELL, SELP, SELPLG, SEMi,SEMA3A, SEMA3B, SEMA3C, SEMA3D, SEMA3E, SEMA3F, SEMA3G, SEMA4A, SEMA4B,SEMA4C, SEMA4D, SEMA4F, SEMA4G, SEMA5A, SEMA5B, SEMA6A, SEMA6B, SEMA6C,SEMA6D, SEMA7A, SEMG1, SEMG2, SENP1, SENP2, SENP3, SENP3-EIF4A1, SENP5,SENP6, SENP7, SENP8, SEPHS1, SEPHS2, SEPSECS, SEPT1, SEPT10, SEPT11,SEPT12, SEPT14, SEPT2, SEPT3, SEPT4, SEPT5, SEPT6, SEPT7, SEPT8, SEPT9,SERAC1, SERBP1, SERF1A, SERF1B, SERF2, SERGEF, SERHL2, SERINC1, SERINC2,SERINC3, SERINC4, SERINC5, SERP1, SERP2, SERPINA1, SERPINA10, SERPINA11,SERPINA12, SERPINA2, SERPINA3, SERPINA4, SERPINA5, SERPINA6, SERPINA7,SERPINA9, SERPINB1, SERPINB10, SERPINB11, SERPINB12, SERPINB13,SERPINB2, SERPINB3, SERPINB4, SERPINB5, SERPINB6, SERPINB7, SERPINB8,SERPINB9, SERPINC1, SERPIND1, SERPINEl, SERPINE2, SERPINE3, SERPINF1,SERPINF2, SERPINGI, SERPINHI, SERPINIl, SERPINI2, SERTADI, SERTAD2,SERTAD3, SERTAD4, SERTM1, SESN1, SESN2, SESN3, SESTD1, SET, SETBP1,SETD1A, SETD1B, SETD2, SETD3, SETD4, SETD5, SETD6, SETD7, SETD9, SETDB1,SETDB2, SETMAR, SETSIP, SETX, SEZ6, SEZ6L, SEZ6L2, SF1, SF3A1, SF3A2,SF3A3, SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, SFI1, SFMBT1, SFMBT2,SFN, SFPQ, SFR1, SFRP1, SFRP2, SFRP4, SFRP5, SFSWAP, SFT2D1, SFT2D2,SFT2D3, SFTA2, SFTA3, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SFXN1, SFXN2,SFXN3, SFXN4, SFXN5, SGCA, SGCB, SGCD, SGCE, SGCG, SGCZ, SGF29, SGIP1,SGK1, SGK2, SGK3, SGK494, SGMS1, SGMS2, SGO1, SG02, SGPL1, SGPP1, SGPP2,SGSH, SGSM1, SGSM2, SGSM3, SGTA, SGTB, SH2B1, SH2B2, SH2B3, SH2D1A,SH2D1B, SH2D2A, SH2D3A, SH2D3C, SH2D4A, SH2D4B, SH2D5, SH2D6, SH2D7,SH3BGR, SH3BGRL, SH3BGRL2, SH3BGRL3, SH3BP1, SH3BP2, SH3BP4, SH3BP5,SH3BP5L, SH3D19, SH3D21, SH3GL1, SH3GL2, SH3GL3, SH3GLB1, SH3GLB2,SH3KBP1, SH3PXD2A, SH3PXD2B, SH3RF1, SH3RF2, SH3RF3, SH3TC1, SH3TC2,SH3YL1, SHANKI, SHANK2, SHANK3, SHARPIN, SHB, SHBG, SHC1, SHC2, SHC3,SHC4, SHCBP1, SHCBP1L, SHD, SHE, SHF, SHH, SHISA2, SHISA3, SHISA4,SHISA5, SHISA6, SHISA7, SHISA8, SHISA9, SHKBP1, SHMT1, SHMT2, SHOC2,SHOX, SHOX2, SHPK, SHPRH, SHQ1, SHROOMI, SHROOM2, SHROOM3, SHROOM4,SHTN1, SI, SIAE, SIAH1, SIAH2, SIAH3, SIDT1, SIDT2, SIGIRR, SIGLECI,SIGLEC10, SIGLEC11, SIGLEC12, SIGLEC14, SIGLEC15, SIGLEC5, SIGLEC6,SIGLEC7, SIGLEC8, SIGLEC9, SIGLECLI, SIGMARI, SIK1, SIK2, SIK3, SIKE1,SIL1, SIM1, SIM2, SIMC1, SIN3A, SIN3B, SIPA1, SIPA1L1, SIPA1L2, SIPA1L3,SIRPA, SIRPB1, SIRPB2, SIRPD, SIRPG, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5,SIRT6, SIRT7, SIT1, SIVA1, SIX1, SIX2, SIX3, SIX4, SIX5, SIX6, SKAl,SKA2, SKA3, SKAP1, SKAP2, SKI, SKIDA1, SKIL, SKIV2L, SKIV2L2, SKOR1,SKOR2, SKP1, SKP2, SLA, SLA2, SLAINI, SLAIN2, SLAMFI, SLAMF6, SLAMF7,SLAMF8, SLAMF9, SLBP, SLC10A1, SLC10A2, SLC10A3, SLC10A4, SLC10A5,SLC10A6, SLC10A7, SLC11A1, SLC11A2, SLC12A1, SLC12A2, SLC12A3, SLC12A4,SLC12A5, SLC12A6, SLC12A7, SLC12A8, SLC12A9, SLC13A1, SLC13A2, SLC13A3,SLC13A4, SLC13A5, SLC14A1, SLC14A2, SLC15A1, SLC15A2, SLC15A3, SLC15A4,SLC15A5, SLC16A1, SLC16A10, SLC16A11, SLC16A12, SLC16A13, SLC16A14,SLC16A2, SLC16A3, SLC16A4, SLC16A5, SLC16A6, SLC16A7, SLC16A8, SLC16A9,SLC17A1, SLC17A2, SLC17A3, SLC17A4, SLC17A5, SLC17A6, SLC17A7, SLC17A8,SLC17A9, SLC18A1, SLC18A2, SLC18A3, SLC18B1, SLC19A1, SLC19A2, SLC19A3,SLC1A1, SLC1A2, SLC1A3, SLC1A4, SLC1A5, SLC1A6, SLC1A7, SLC20A1,SLC20A2, SLC22A1, SLC22A10, SLC22A11, SLC22A12, SLC22A13, SLC22A14,SLC22A15, SLC22A16, SLC22A17, SLC22A18, SLC22A18AS, SLC22A2, SLC22A23,SLC22A24, SLC22A25, SLC22A3, SLC22A31, SLC22A4, SLC22A5, SLC22A6,SLC22A7, SLC22A8, SLC22A9, SLC23A1, SLC23A2, SLC23A3, SLC24A1, SLC24A2,SLC24A3, SLC24A4, SLC24A5, SLC25A1, SLC25A10, SLC25A11, SLC25A12,SLC25A13, SLC25A14, SLC25A15, SLC25A16, SLC25A17, SLC25A18, SLC25A19,SLC25A2, SLC25A20, SLC25A21, SLC25A22, SLC25A23, SLC25A24, SLC25A25,SLC25A26, SLC25A27, SLC25A28, SLC25A29, SLC25A3, SLC25A30, SLC25A31,SLC25A32, SLC25A33, SLC25A34, SLC25A35, SLC25A36, SLC25A37, SLC25A38,SLC25A39, SLC25A4, SLC25A40, SLC25A41, SLC25A42, SLC25A43, SLC25A44,SLC25A45, SLC25A46, SLC25A47, SLC25A48, SLC25A5, SLC25A51, SLC25A52,SLC25A53, SLC25A6, SLC26A1, SLC26A10, SLC26A11, SLC26A2, SLC26A3,SLC26A4, SLC26A5, SLC26A6, SLC26A7, SLC26A8, SLC26A9, SLC27A1, SLC27A2,SLC27A3, SLC27A4, SLC27A5, SLC27A6, SLC28A1, SLC28A2, SLC28A3, SLC29A1,SLC29A2, SLC29A3, SLC29A4, SLC2A1, SLC2A10, SLC2A11, SLC2A12, SLC2A13,SLC2A14, SLC2A2, SLC2A3, SLC2A4, SLC2A4RG, SLC2A5, SLC2A6, SLC2A7,SLC2A8, SLC2A9, SLC30A1, SLC30A10, SLC30A2, SLC30A3, SLC30A4, SLC30A5,SLC30A6, SLC30A7, SLC30A8, SLC30A9, SLC31A1, SLC31A2, SLC32A1, SLC33A1,SLC34A1, SLC34A2, SLC34A3, SLC35A1, SLC35A2, SLC35A3, SLC35A4, SLC35A5,SLC35B1, SLC35B2, SLC35B3, SLC35B4, SLC35C1, SLC35C2, SLC35D1, SLC35D2,SLC35D3, SLC35E1, SLC35E2, SLC35E2B, SLC35E3, SLC35E4, SLC35F1, SLC35F2,SLC35F3, SLC35F4, SLC35F5, SLC35F6, SLC35G1, SLC35G2, SLC35G3, SLC35G4,SLC35G5, SLC35G6, SLC36A1, SLC36A2, SLC36A3, SLC36A4, SLC37A1, SLC37A2,SLC37A3, SLC37A4, SLC38A1, SLC38A10, SLC38A11, SLC38A2, SLC38A3,SLC38A4, SLC38A5, SLC38A6, SLC38A7, SLC38A8, SLC38A9, SLC39A1, SLC39A10,SLC39A11, SLC39A12, SLC39A13, SLC39A14, SLC39A2, SLC39A3, SLC39A4,SLC39A5, SLC39A6, SLC39A7, SLC39A8, SLC39A9, SLC3A1, SLC3A2, SLC40A1,SLC41A1, SLC41A2, SLC41A3, SLC43A1, SLC43A2, SLC43A3, SLC44A1, SLC44A2,SLC44A3, SLC44A4, SLC44A5, SLC45A1, SLC45A2, SLC45A3, SLC45A4, SLC46A1,SLC46A2, SLC46A3, SLC47A1, SLC47A2, SLC48A1, SLC4A1, SLC4A10, SLC4A11,SLC4A1AP, SLC4A2, SLC4A3, SLC4A4, SLC4A5, SLC4A7, SLC4A8, SLC4A9,SLC50A1, SLC51A, SLC51B, SLC52A1, SLC52A2, SLC52A3, SLC5A1, SLC5A10,SLC5A11, SLC5A12, SLC5A2, SLC5A3, SLC5A4, SLC5A5, SLC5A6, SLC5A7,SLC5A8, SLC5A9, SLC6A1, SLC6A11, SLC6A12, SLC6A13, SLC6A14, SLC6A15,SLC6A16, SLC6A17, SLC6A18, SLC6A19, SLC6A2, SLC6A20, SLC6A3, SLC6A4,SLC6A5, SLC6A6, SLC6A7, SLC6A8, SLC6A9, SLC7A1, SLC7A10, SLC7A11,SLC7A13, SLC7A14, SLC7A2, SLC7A3, SLC7A4, SLC7A5, SLC7A6, SLC7A6OS,SLC7A7, SLC7A8, SLC7A9, SLC8A1, SLC8A2, SLC8A3, SLC8B1, SLC9A1, SLC9A2,SLC9A3, SLC9A3R1, SLC9A3R2, SLC9A4, SLC9A5, SLC9A6, SLC9A7, SLC9A8,SLC9A9, SLC9B1, SLC9B2, SLC9C1, SLC9C2, SLCO1A2, SLCO1B1, SLCO1B3,SLCO1B7, SLCO1C1, SLCO2A1, SLCO2B1, SLCO3A1, SLCO4A1, SLCO4C1, SLCO5A1,SLCO6A1, SLF1, SLF2, SLFN11, SLFN12, SLFN12L, SLFN13, SLFN14, SLFN5,SLFNL1, SLIRP, SLIT1, SLIT2, SLIT3, SLITRK1, SLITRK2, SLITRK3, SLITRK4,SLITRK5, SLITRK6, SLK, SLMAP, SLN, SLPI, SL™, SLU7, SLURPI, SLURP2,SLX1A, SLX1B, SLX4, SLX4IP, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6,SMAD7, SMAD9, SMAGP, SMAP1, SMAP2, SMARCA1, SMARCA2, SMARCA4, SMARCA5,SMARCAD1, SMARCAL1, SMARCB1, SMARCC1, SMARCC2, SMARCD1, SMARCD2,SMARCD3, SMARCEl, SMC1A, SMC1B, SMC2, SMC3, SMC4, SMC5, SMC6, SMCHD1,SMCO1, SMCO2, SMCO3, SMCO4, SMCP, SMCR8, SMDT1, SMG1, SMG5, SMG6, SMG7,SMG8, SMG9, SMIM1, SMIM10, SMIM10L1, SMIM10L2A, SMIM10L2B, SMIM11A,SMIM11B, SMIM12, SMIM13, SMIM14, SMIM15, SMIM17, SMIM18, SMIM19, SMIM2,SMIM20, SMIM21, SMIM22, SMIM23, SMIM24, SMIM26, SMIM27, SMIM28, SMIM29,SMIM3, SMIM30, SMIM31, SMIM4, SMIM5, SMIM6, SMIM7, SMIM8, SMIM9, SMKR1,SMLR1, SMN1, SMN2, SMNDC1, SMO, SMOC1, SMOC2, SMOX, SMPD1, SMPD2, SMPD3,SMPD4, SMPDL3A, SMPDL3B, SMPX, SMR3A, SMR3B, SMS, SMTN, SMTNL1, SMTNL2,SMU1, SMUG1, SMURFI, SMURF2, SMYD1, SMYD2, SMYD3, SMYD4, SMYD5, SNAIl,SNAI2, SNAI3, SNAP23, SNAP25, SNAP29, SNAP47, SNAP91, SNAPC1, SNAPC2,SNAPC3, SNAPC4, SNAPC5, SNAPIN, SNCA, SNCAIP, SNCB, SNCG, SND1, SNED1,SNF8, SNHG28, SNIP1, SNN, SNPH, SNRK, SNRNP200, SNRNP25, SNRNP27,SNRNP35, SNRNP40, SNRNP48, SNRNP70, SNRPA, SNRPA1, SNRPB, SNRPB2, SNRPC,SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, SNRPN, SNTA1, SNTB1, SNTB2,SNTG1, SNTG2, SNTN, SNU13, SNUPN, SNURF, SNW1, SNX1, SNX10, SNX11,SNX12, SNX13, SNX14, SNX15, SNX16, SNX17, SNX18, SNX19, SNX2, SNX20,SNX21, SNX22, SNX24, SNX25, SNX27, SNX29, SNX3, SNX30, SNX31, SNX32,SNX33, SNX4, SNX5, SNX6, SNX7, SNX8, SNX9, SOAT1, SOAT2, SOBP, SOCS1,SOCS2, SOCS3, SOCS4, SOCS5, SOCS6, SOCS7, SOD1, SOD2, SOD3, SOGA1,SOGA3, SOHLH1, SOHLH2, SON, SORBS1, SORBS2, SORBS3, SORCS1, SORCS2,SORCS3, SORD, SORL1, SORT1, SOS1, SOS2, SOST, SOSTDC1, SOWAHA, SOWAHB,SOWAHC, SOWAHD, SOX1, SOX10, SOX11, SOX12, SOX13, SOX14, SOX15, SOX17,SOX18, SOX2, SOX21, SOX3, SOX30, SOX4, SOX5, SOX6, SOX7, SOX8, SOX9,SP1, SP100, SP110, SP140, SP140L, SP2, SP3, SP4, SP5, SP6, SP7, SP8,SP9, SPA17, SPAAR, SPACA1, SPACA3, SPACA4, SPACA5, SPACA5B, SPACA6,SPACA7, SPACA9, SPAG1, SPAGI1A, SPAGI1B, SPAG16, SPAG17, SPAG4, SPAG5,SPAG6, SPAG7, SPAG8, SPAG9, SPAM1, SPANXA1, SPANXA2, SPANXB1, SPANXC,SPANXD, SPANXN1, SPANXN2, SPANXN3, SPANXN4, SPANXN5, SPARC, SPARCL1,SPART, SPAST, SPATA1, SPATA12, SPATA13, SPATA16, SPATA17, SPATA18,SPATA19, SPATA2, SPATA20, SPATA21, SPATA22, SPATA24, SPATA25, SPATA2L,SPATA3, SPATA31A1, SPATA31A3, SPATA31A5, SPATA31A6, SPATA31A7,SPATA3ID1, SPATA31D3, SPATA31D4, SPATA31E1, SPATA32, SPATA33, SPATA4,SPATA45, SPATA46, SPATA5, SPATA5L1, SPATA6, SPATA6L, SPATA7, SPATA8,SPATA9, SPATC1, SPATC1L, SPATS1, SPATS2, SPATS2L, SPC24, SPC25, SPCS1,SPCS2, SPCS3, SPDEF, SPDL1, SPDYA, SPDYC, SPDYEl, SPDYE16, SPDYE2,SPDYE2B, SPDYE3, SPDYE4, SPDYE5, SPDYE6, SPECCI, SPECCIL,SPECC1L-ADORA2A, SPEF1, SPEF2, SPEG, SPEM1, SPEN, SPERT, SPESPI, SPG11,SPG21, SPG7, SPHAR, SPHK1, SPHK2, SPHKAP, SPIl, SPIB, SPIC, SPICE1,SPIDR, SPIN1, SPIN2A, SPIN2B, SPIN3, SPIN4, SPINKI, SPINK13, SPINK14,SPINK2, SPINK4, SPINK5, SPINK6, SPINK7, SPINK8, SPINK9, SPINTI, SPINT2,SPINT3, SPINT4, SPIRE1, SPIRE2, SPN, SPNS1, SPNS2, SPNS3, SPO11, SPOCD1,SPOCKI, SPOCK2, SPOCK3, SPON1, SPON2, SPOP, SPOPL, SPOUTI, SPP1, SPP2,SPPL2A, SPPL2B, SPPL2C, SPPL3, SPR, SPREDI, SPRED2, SPRED3, SPRN,SPRR1A, SPRR1B, SPRR2A, SPRR2B, SPRR2D, SPRR2E, SPRR2F, SPRR2G, SPRR3,SPRR4, SPRR5, SPRTN, SPRY1, SPRY2, SPRY3, SPRY4, SPRYD3, SPRYD4, SPRYD7,SPSB1, SPSB2, SPSB3, SPSB4, SPTA1, SPTAN1, SPTB, SPTBN1, SPTBN2, SPTBN4,SPTBN5, SPTLC1, SPTLC2, SPTLC3, SPTSSA, SPTSSB, SPTY2D1, SPTY2D1-AS1,SPX, SPZ1, SQLE, SQOR, SQSTM1, SRA1, SRBD1, SRC, SRCAP, SRCIN1, SRD5A1,SRD5A2, SRD5A3, SREBF1, SREBF2, SREK1, SREK1IP1, SRF, SRFBP1, SRGAP1,SRGAP2, SRGAP2B, SRGAP2C, SRGAP3, SRGN, SRI, SRL, SRM, SRMS, SRP14,SRP19, SRP54, SRP68, SRP72, SRP9, SRPK1, SRPK2, SRPK3, SRPRA, SRPRB,SRPX, SRPX2, SRR, SRRD, SRRM1, SRRM2, SRRM3, SRRM4, SRRM5, SRRT, SRSF1,SRSF10, SRSF 11, SRSF12, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7,SRSF8, SRSF9, SRXN1, SRY, SS18, SS18L1, SS18L2, SSB, SSBP1, SSBP2,SSBP3, SSBP4, SSC4D, SSC5D, SSFA2, SSH1, SSH2, SSH3, SSMEM1, SSNA1,SSPN, SSPO, SSR1, SSR2, SSR3, SSR4, SSRP1, SSSCA1, SST, SSTR1, SSTR2,SSTR3, SSTR4, SSTR5, SSU72, SSU72P8, SSUH2, SSX1, SSX2, SSX2B, SSX2IP,SSX3, SSX4, SSX4B, SSX5, SSX7, ST13, ST14, ST18, ST20, ST20-MTHFS,ST3GAL1, ST3GAL2, ST3GAL3, ST3GAL4, ST3GAL5, ST3GAL6, ST5, ST6GAL1,ST6GAL2, ST6GALNAC1, ST6GALNAC2, ST6GALNAC3, ST6GALNAC4, ST6GALNAC5,ST6GALNAC6, ST7, ST7L, ST8SIA1, ST8SIA2, ST8SIA3, ST8SIA4, ST8SIA5,ST8SIA6, STAB1, STAB2, STAC, STAC2, STAC3, STAG1, STAG2, STAG3, STAM,STAM2, STAMBP, STAMBPL1, STAP1, STAP2, STAR, STARD10, STARD13, STARD3,STARD3NL, STARD4, STARD5, STARD6, STARD7, STARD8, STARD9, STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, STAT6, STATH, STAU1, STAU2, STBD1, STC1,STC2, STEAPI, STEAPIB, STEAP2, STEAP3, STEAP4, STH, STIL, STIM1, STIM2,STIP1, STK10, STK11, STK11IP, STK16, STK17A, STK17B, STK19, STK24,STK25, STK26, STK3, STK31, STK32A, STK32B, STK32C, STK33, STK35, STK36,STK38, STK38L, STK39, STK4, STK40, STKLD1, STMN1, STMN2, STMN3, STMN4,STMND1, STN1, STOM, STOMLI, STOML2, STOML3, STON1, STON1-GTF2A1L, STON2,STOX1, STOX2, STPG1, STPG2, STPG3, STPG4, STRA6, STRA8, STRADA, STRADB,STRAP, STRBP, STRC, STRIP1, STRIP2, STRN, STRN3, STRN4, STS, STT3A,STT3B, STUB1, STUM, STX10, STX11, STX12, STX16, STX16-NPEPL1, STX17,STX18, STX19, STX1A, STX1B, STX2, STX3, STX4, STX5, STX6, STX7, STX8,STXBP1, STXBP2, STXBP3, STXBP4, STXBP5, STXBP5L, STXBP6, STYK1, STYX,STYXL1, SUB1, SUCLA2, SUCLG1, SUCLG2, SUCNR1, SUCO, SUDS3, SUFU, SUGCT,SUGP1, SUGP2, SUGT1, SULF1, SULF2, SULTIA1, SULT1A2, SULT1A3, SULT1A4,SULTIBI, SULT1C2, SULT1C3, SULT1C4, SULTIEl, SULT2A1, SULT2B1, SULT4A1,SULT6B1, SUMF1, SUMF2, SUMO1, SUMO2, SUMO3, SUMO4, SUN1, SUN2, SUN3,SUN5, SUOX, SUPT16H, SUPT20H, SUPT3H, SUPT4H1, SUPT5H, SUPT6H, SUPT7L,SUPV3L1, SURF1, SURF2, SURF4, SURF6, SUSD1, SUSD2, SUSD3, SUSD4, SUSD5,SUSD6, SUV39H1, SUV39H2, SUZ12, SV2A, SV2B, SV2C, SVBP, SVEP1, SVIL,SVIP, SVOP, SVOPL, SWAP70, SWI5, SWSAP1, SWT1, SYAP1, SYBU, SYCEl,SYCE1L, SYCE2, SYCE3, SYCN, SYCP1, SYCP2, SYCP2L, SYCP3, SYDE1, SYDE2,SYF2, SYK, SYMPK, SYN1, SYN2, SYN3, SYNC, SYNCRIP, SYNDIGI, SYNDIGIL,SYNE1, SYNE2, SYNE3, SYNE4, SYNGAPI, SYNGRI, SYNGR2, SYNGR3, SYNGR4,SYNJ1, SYNJ2, SYNJ2BP, SYNJ2BP-COX16, SYNM, SYNPO, SYNPO2, SYNPO2L,SYNPR, SYNRG, SYP, SYPL1, SYPL2, SYS1, SYS1-DBNDD2, SYT1, SYT10, SYT11,SYT12, SYT13, SYT14, SYT15, SYT16, SYT17, SYT2, SYT3, SYT4, SYT5, SYT6,SYT7, SYT8, SYT9, SYTL1, SYTL2, SYTL3, SYTL4, SYTL5, SYVN1, SZRD1, SZT2,T, TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAB1, TAB2, TAB3, TACl,TAC3, TAC4, TACC1, TACC2, TACC3, TACO1, TACR1, TACR2, TACR3, TACSTD2,TADA1, TADA2A, TADA2B, TADA3, TAF1, TAF10, TAF11, TAF12, TAF13, TAF15,TAFlA, TAF1B, TAF1C, TAF1D, TAF1L, TAF2, TAF3, TAF4, TAF4B, TAF5, TAF5L,TAF6, TAF6L, TAF7, TAF7L, TAF8, TAF9, TAF9B, TAGAP, TAGLN, TAGLN2,TAGLN3, TAL1, TAL2, TALDO1, TAMM41, TANC1, TANC2, TANGO2, TANGO6, TANK,TAOK1, TAOK2, TAOK3, TAP1, TAP2, TAPBP, TAPBPL, TAPT1, TARBP1, TARBP2,TARDBP, TARM1, TARS, TARS2, TARSL2, TAS1R1, TAS1R2, TAS1R3, TAS2R1,TAS2R10, TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30,TAS2R31, TAS2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41, TAS2R42, TAS2R43,TAS2R46, TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TASP1, TAT,TATDN1, TATDN2, TATDN3, TAXIBPI, TAX1BP3, TAZ, TBATA, TBC1D1, TBC1D10A,TBC1D10B, TBC1D10C, TBC1D12, TBC1D13, TBC1D14, TBC1D15, TBC1D16,TBC1D17, TBC1D19, TBC1D2, TBC1D20, TBC1D21, TBC1D22A, TBC1D22B, TBC1D23,TBC1D24, TBC1D25, TBC1D26, TBC1D28, TBC1D29, TBC1D2B, TBC1D3, TBC1D30,TBC1D31, TBC1D32, TBC1D3B, TBC1D3C, TBC1D3D, TBC1D3E, TBC1D3F, TBC1D3G,TBC1D3H, TBC1D3I, TBC1D3K, TBC1D3L, TBC1D4, TBC1D5, TBC1D7, TBC1D8,TBC1D8B, TBC1D9, TBC1D9B, TBCA, TBCB, TBCC, TBCCD1, TBCD, TBCE, TBCEL,TBCK, TBK1, TBKBP1, TBL1X, TBL1XR1, TBL1Y, TBL2, TBL3, TBP, TBPL1,TBPL2, TBR1, TBRG1, TBRG4, TBX1, TBX10, TBX15, TBX18, TBX19, TBX2,TBX20, TBX21, TBX22, TBX3, TBX4, TBX5, TBX6, TBXA2R, TBXAS1, TC2N,TCAF1, TCAF2, TCAIM, TCAP, TCEA1, TCEA2, TCEA3, TCEAL1, TCEAL2, TCEAL3,TCEAL4, TCEAL5, TCEAL6, TCEAL7, TCEAL8, TCEAL9, TCEANC, TCEANC2, TCERG1,TCERG1L, TCF12, TCF15, TCF19, TCF20, TCF21, TCF23, TCF24, TCF25, TCF3,TCF4, TCF7, TCF7L1, TCF7L2, TCFL5, TCHH, TCHHL1, TCHP, TCIRG1, TCL1A,TCL1B, TCN1, TCN2, TCOF1, TCP1, TCP10, TCP10L, TCP10L2, TCP11, TCP11L1,TCP11L2, TCP11X2, TCTA, TCTE1, TCTE3, TCTEX1D1, TCTEX1D2, TCTEX1D4,TCTN1, TCTN2, TCTN3, TDG, TDGF1, TDO2, TDP1, TDP2, TDRD1, TDRD10,TDRD12, TDRD15, TDRD3, TDRD5, TDRD6, TDRD7, TDRD9, TDRKH, TDRP, TEAD1,TEAD2, TEAD3, TEAD4, TEC, TECPR1, TECPR2, TECR, TECRL, TECTA, TECTB,TEDDM1, TEF, TEFM, TEK, TEKT1, TEKT2, TEKT3, TEKT4, TEKT5, TELO2, TEN1,TEN1-CDK3, TENM1, TENM2, TENM3, TENM4, TEP1, TEPP, TEPSIN, TERB1, TERB2,TERF1, TERF2, TERF2IP, TERT, TES, TESC, TESK1, TESK2, TESMIN, TESPA1,TET1, TET2, TET3, TEX10, TEX101, TEX11, TEX12, TEX13A, TEX13B, TEX13C,TEX13D, TEX14, TEX15, TEX19, TEX2, TEX22, TEX26, TEX261, TEX264, TEX28,TEX29, TEX30, TEX33, TEX35, TEX36, TEX37, TEX38, TEX43, TEX44, TEX45,TEX46, TEX47, TEX48, TEX49, TEX50, TEX51, TEX9, TF, TFAM, TFAP2A,TFAP2B, TFAP2C, TFAP2D, TFAP2E, TFAP4, TFB1M, TFB2M, TFCP2, TFCP2L1,TFDP1, TFDP2, TFDP3, TFE3, TFEB, TFEC, TFF1, TFF2, TFF3, TFG, TFIP11,TFPI, TFPI2, TFPT, TFR2, TFRC, TG, TGDS, TGFA, TGFB1, TGFB1I1, TGFB2,TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, TGFBR3L, TGFBRAP1, TGIF1, TGIF2,TGIF2-C20orf24, TGIF2LX, TGIF2LY, TGM1, TGM2, TGM3, TGM4, TGM5, TGM6,TGM7, TGOLN2, TGS1, TH, THADA, THAP1, THAP10, THAPi11, THAP12, THAP2,THAP3, THAP4, THAP5, THAP6, THAP7, THAP8, THAP9, THBD, THBS1, THBS2,THBS3, THBS4, THEG, THEGL, THEM4, THEM5, THEM6, THEMIS, THEMIS2, THG1L,THNSL1, THNSL2, THOC1, THOC2, THOC3, THOC5, THOC6, THOC7, THOP1, THPO,THRA, THRAP3, THRB, THRSP, THSD1, THSD4, THSD7A, THSD7B, THTPA, THUMPD1,THUMPD2, THUMPD3, THY1, THYN1, TIAl, TIAF1, TIAL1, TIAM1, TIAM2, TICAMI,TICAM2, TICRR, TIEl, TIFA, TIFAB, TIGAR, TIGD1, TIGD2, TIGD3, TIGD4,TIGD5, TIGD6, TIGD7, TIGIT, TIMD4, TIMELESS, TIMM10, TIMM10B, TIMM13,TIMM17A, TIMM17B, TIMM21, TIMM22, TIMM23, TIMM23B, TIMM29, TIMM44,TIMM50, TIMM8A, TIMM8B, TIMM9, TIMMDC1, TIMP1, TIMP2, TIMP3, TIMP4,TINAG, TINAGL1, TINCR, TINF2, TIPARP, TIPIN, TIPRL, TIRAP, TISP43,TJAP1, TJP1, TJP2, TJP3, TK1, TK2, TKFC, TKT, TKTL1, TKTL2, TLCD1,TLCD2, TLDC1, TLDC2, TLE1, TLE2, TLE3, TLE4, TLE6, TLK1, TLK2, TLL1,TLL2, TLN1, TLN2, TLNRD1, TLR1, TLR10, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLX1, TLX2, TLX3, TM2D1, TM2D2, TM2D3, TM4SF1,TM4SF18, TM4SF19, TM4SF19-TCTEX1D2, TM4SF20, TM4SF4, TM4SF5, TM6SF1,TM6SF2, TM7SF2, TM7SF3, TM9SF1, TM9SF2, TM9SF3, TM9SF4, TMA16, TMA7,TMBIM1, TMBIM4, TMBIM6, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8,TMCC1, TMCC2, TMCC3, TMCO1, TMCO2, TMCO3, TMCO4, TMCO5A, TMCO6, TMED1,TMED10, TMED2, TMED3, TMED4, TMED5, TMED6, TMED7, TMED7-TICAM2, TMED8,TMED9, TMEFF1, TMEFF2, TMEM100, TMEM101, TMEM102, TMEM104, TMEM105,TMEM106A, TMEM106B, TMEM106C, TMEM107, TMEM108, TMEM109, TMEM11,TMEM110, TMEM110-MUSTN1, TMEM 114, TMEM115, TMEM116, TMEM117, TMEM119,TMEM120A, TMEM120B, TMEM121, TMEM121B, TMEM123, TMEM125, TMEM126A,TMEM126B, TMEM127, TMEM128, TMEM129, TMEM130, TMEM131, TMEM131L,TMEM132A, TMEM132B, TMEM132C, TMEM132D, TMEM132E, TMEM133, TMEM134,TMEM135, TMEM136, TMEM138, TMEM139, TMEM140, TMEM141, TMEM143, TMEM144,TMEM145, TMEM147, TMEM14A, TMEM14B, TMEM14C, TMEM150A, TMEM150B,TMEM150C, TMEM151A, TMEM151B, TMEM154, TMEM155, TMEM156, TMEM158,TMEM159, TMEM160, TMEM161A, TMEM161B, TMEM163, TMEM164, TMEM165,TMEM167A, TMEM167B, TMEM168, TMEM169, TMEM17, TMEM170A, TMEM170B,TMEM171, TMEM173, TMEM174, TMEM175, TMEM176A, TMEM176B, TMEM177,TMEM178A, TMEM178B, TMEM179, TMEM179B, TMEM18, TMEM181, TMEM182,TMEM183A, TMEM184A, TMEM184B, TMEM184C, TMEM185A, TMEM185B, TMEM186,TMEM187, TMEM189, TMEM189-UBE2V1, TMEM19, TMEM190, TMEM191B, TMEM191C,TMEM192, TMEM196, TMEM198, TMEM199, TMEM2, TMEM200A, TMEM200B, TMEM200C,TMEM201, TMEM202, TMEM203, TMEM204, TMEM205, TMEM206, TMEM207, TMEM208,TMEM209, TMEM210, TMEM211, TMEM212, TMEM213, TMEM214, TMEM215, TMEM216,TMEM217, TMEM218, TMEM219, TMEM220, TMEM221, TMEM222, TMEM223, TMEM225,TMEM225B, TMEM229A, TMEM229B, TMEM230, TMEM231, TMEM232, TMEM233,TMEM234, TMEM235, TMEM236, TMEM237, TMEM238, TMEM239, TMEM240, TMEM241,TMEM242, TMEM243, TMEM244, TMEM245, TMEM246, TMEM247, TMEM248, TMEM249,TMEM25, TMEM250, TMEM251, TMEM252, TMEM253, TMEM254, TMEM255A, TMEM255B,TMEM256, TMEM256-PLSCR3, TMEM257, TMEM258, TMEM259, TMEM26, TMEM260,TMEM262, TMEM263, TMEM265, TMEM266, TMEM267, TMEM268, TMEM269, TMEM27,TMEM270, TMEM30A, TMEM30B, TMEM31, TMEM33, TMEM35A, TMEM35B, TMEM37,TMEM38A, TMEM38B, TMEM39A, TMEM39B, TMEM40, TMEM41A, TMEM41B, TMEM42,TMEM43, TMEM44, TMEM45A, TMEM45B, TMEM47, TMEM5, TMEM50A, TMEM50B,TMEM51, TMEM52, TMEM52B, TMEM53, TMEM54, TMEM55A, TMEM55B, TMEM56,TMEM56-RWDD3, TMEM57, TMEM59, TMEM59L, TMEM60, TMEM61, TMEM62, TMEM63A,TMEM63B, TMEM63C, TMEM64, TMEM65, TMEM67, TMEM68, TMEM69, TMEM70,TMEM71, TMEM72, TMEM74, TMEM74B, TMEM78, TMEM79, TMEM80, TMEM81, TMEM82,TMEM86A, TMEM86B, TMEM87A, TMEM87B, TMEM88, TMEM88B, TMEM89, TMEM8A,TMEM8B, TMEM9, TMEM91, TMEM92, TMEM94, TMEM95, TMEM97, TMEM98, TMEM99,TMEM9B, TMF1, TMIE, TMIGD1, TMIGD2, TMIGD3, TMLHE, TMOD1, TMOD2, TMOD3,TMOD4, TMPO, TMPPE, TMPRSS11A, TMPRSS11B, TMPRSS11D, TMPRSS11E,TMPRSS11F, TMPRSS12, TMPRSS13, TMPRSS15, TMPRSS2, TMPRSS3, TMPRSS4,TMPRSS4-AS1, TMPRSS5, TMPRSS6, TMPRSS7, TMPRSS9, TMSB10, TMSB15A,TMSB15B, TMSB4X, TMSB4Y, TMTC1, TMTC2, TMTC3, TMTC4, TMUB1, TMUB2, TMX1,TMX2, TMX2-CTNND1, TMX3, TMX4, TNC, TNF, TNFAIP1, TNFAIP2, TNFAIP3,TNFAIP6, TNFAIP8, TNFAIP8L1, TNFAIP8L2, TNFAIP8L3, TNFRSF10A, TNFRSF10B,TNFRSF10C, TNFRSF10D, TNFRSF 11A, TNFRSF11B, TNFRSF12A, TNFRSF13B,TNFRSF13C, TNFRSF14, TNFRSF17, TNFRSF18, TNFRSF19, TNFRSFlA, TNFRSFlB,TNFRSF21, TNFRSF25, TNFRSF4, TNFRSF6B, TNFRSF8, TNFRSF9, TNFSF10,TNFSF11, TNFSF12, TNFSF12-TNFSF13, TNFSF13, TNFSF13B, TNFSF14, TNFSF15,TNFSF18, TNFSF4, TNFSF8, TNFSF9, TNIK, TNIP1, TNIP2, TNIP3, TNK1, TNK2,TNKS, TNKS1BP1, TNKS2, TNMD, TNN, TNNC1, TNNC2, TNNIl, TNNI2, TNNI3,TNNI3K, TNNT1, TNNT2, TNNT3, TNP1, TNP2, TNPO1, TNPO2, TNPO3, TNR,TNRC18, TNRC6A, TNRC6B, TNRC6C, TNS1, TNS2, TNS3, TNS4, TNXB, TOBI,TOB2, TOE1, TOGARAMI, TOGARAM2, TOLLIP, TOMI, TOMIL1, TOM1L2, TOMM20,TOMM20L, TOMM22, TOMM34, TOMM40, TOMM40L, TOMM5, TOMM6, TOMM7, TOMM70,TONSL, TOPI, TOP1MT, TOP2A, TOP2B, TOP3A, TOP3B, TOPAZ1, TOPBP1, TOPORS,TOR1A, TOR1AIP1, TOR1AIP2, TORIB, TOR2A, TOR3A, TOR4A, TOX, TOX2, TOX3,TOX4, TP53, TP53AIP1, TP53BP1, TP53BP2, TP5311l, TP53I13, TP53I3,TP53INP1, TP53INP2, TP53RK, TP53TG3, TP53TG3B, TP53TG3C, TP53TG3D,TP53TG3E, TP53TG3F, TP53TG5, TP63, TP73, TPBG, TPBGL, TPCN1, TPCN2,TPD52, TPD52L1, TPD52L2, TPD52L3, TPGS1, TPGS2, TPH1, TPH2, TPIl, TPK1,TPM1, TPM2, TPM3, TPM4, TPMT, TPO, TPP1, TPP2, TPPP, TPPP2, TPPP3, TPR,TPRA1, TPRG1, TPRG1L, TPRKB, TPRN, TPRX1, TPSAB1, TPSB2, TPSD1, TPSG1,TPST1, TPST2, TPT1, TPTE, TPTE2, TPX2, TRA2A, TRA2B, TRABD, TRABD2A,TRABD2B, TRAC, TRADD, TRAFI, TRAF2, TRAF3, TRAF3IP1, TRAF3IP2, TRAF3IP3,TRAF4, TRAF5, TRAF6, TRAF7, TRAFD1, TRAIP, TRAJI, TRAJ10, TRAJ11,TRAJ12, TRAJ13, TRAJ14, TRAJ16, TRAJ17, TRAJ18, TRAJ19, TRAJ2, TRAJ20,TRAJ21, TRAJ22, TRAJ23, TRAJ24, TRAJ25, TRAJ26, TRAJ27, TRAJ28, TRAJ29,TRAJ3, TRAJ30, TRAJ31, TRAJ32, TRAJ33, TRAJ34, TRAJ35, TRAJ36, TRAJ37,TRAJ38, TRAJ39, TRAJ4, TRAJ40, TRAJ41, TRAJ42, TRAJ43, TRAJ44, TRAJ45,TRAJ46, TRAJ47, TRAJ48, TRAJ49, TRAJ5, TRAJ50, TRAJ52, TRAJ53, TRAJ54,TRAJ56, TRAJ57, TRAJ58, TRAJ59, TRAJ6, TRAJ61, TRAJ7, TRAJ9, TRAKI,TRAK2, TRAMI, TRAMIL1, TRAM2, TRANKI, TRAP1, TRAPPC1, TRAPPC10,TRAPPC11, TRAPPC12, TRAPPC13, TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L,TRAPPC4, TRAPPC5, TRAPPC6A, TRAPPC6B, TRAPPC8, TRAPPC9, TRATI, TRAV10,TRAV1-1, TRAV1-2, TRAV12-1, TRAV12-2, TRAV12-3, TRAV13-1, TRAV13-2,TRAV14DV4, TRAV16, TRAV17, TRAV18, TRAV19, TRAV2, TRAV20, TRAV21,TRAV22, TRAV23DV6, TRAV24, TRAV25, TRAV26-1, TRAV26-2, TRAV27,TRAV29DV5, TRAV3, TRAV30, TRAV34, TRAV36DV7, TRAV38-1, TRAV38-2DV8,TRAV39, TRAV4, TRAV40, TRAV41, TRAV5, TRAV6, TRAV7, TRAV8-1, TRAV8-2,TRAV8-3, TRAV8-4, TRAV8-6, TRAV8-7, TRAV9-1, TRAV9-2, TRBC2, TRBJ2-1,TRBJ2-2, TRBJ2-2P, TRBJ2-3, TRBJ2-4, TRBJ2-5, TRBJ2-6, TRBJ2-7,TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV19, TRBV2, TRBV20-1,TRBV200R9-2, TRBV210R9-2, TRBV23-1, TRBV230R9-2, TRBV24-1, TRBV25-1,TRBV27, TRBV28, TRBV29-1, TRBV30, TRBV3-1, TRBV4-1, TRBV4-2, TRBV5-1,TRBV5-3, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-7, TRBV6-1, TRBV6-4, TRBV6-5,TRBV6-6, TRBV6-7, TRBV6-8, TRBV7-1, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7,TRBV7-9, TRBV9, TRDC, TRDD1, TRDD2, TRDD3, TRDJ1, TRDJ2, TRDJ3, TRDJ4,TRDMT1, TRDN, TRDV1, TRDV2, TRDV3, TREH, TREM1, TREM2, TREML1, TREML2,TREML4, TRERF1, TREX1, TREX2, TRGC1, TRGC2, TRGJ1, TRGJ2, TRGJP, TRGJP1,TRGJP2, TRGV1, TRGV10, TRGV 11, TRGV2, TRGV3, TRGV4, TRGV5, TRGV8,TRGV9, TRH, TRHDE, TRHR, TRIAP1, TRIB1, TRIB2, TRIB3, TRIL, TRIM10,TRIM11, TRIM13, TRIM14, TRIM15, TRIM16, TRIM16L, TRIM17, TRIM2, TRIM21,TRIM22, TRIM23, TRIM24, TRIM25, TRIM26, TRIM27, TRIM28, TRIM29, TRIM3,TRIM31, TRIM32, TRIM33, TRIM34, TRIM35, TRIM36, TRIM37, TRIM38, TRIM39,TRIM39-RPP21, TRIM4, TRIM40, TRIM41, TRIM42, TRIM43, TRIM43B, TRIM44,TRIM45, TRIM46, TRIM47, TRIM48, TRIM49, TRIM49B, TRIM49C, TRIM49D1,TRIM49D2, TRIM5, TRIM50, TRIM51, TRIM52, TRIM54, TRIM55, TRIM56, TRIM58,TRIM59, TRIM6, TRIM60, TRIM61, TRIM62, TRIM63, TRIM64, TRIM64B, TRIM64C,TRIM65, TRIM66, TRIM67, TRIM68, TRIM69, TRIM6-TRIM34, TRIM7, TRIM71,TRIM72, TRIM73, TRIM74, TRIM75P, TRIM77, TRIM8, TRIM9, TRIML1, TRIML2,TRIO, TRIOBP, TRIP10, TRIP11, TRIP12, TRIP13, TRIP4, TRIP6, TRIQK, TRIR,TRIT1, TRMO, TRMT1, TRMT10A, TRMT10B, TRMT10C, TRMT11, TRMT 112, TRMT12,TRMT13, TRMT1L, TRMT2A, TRMT2B, TRMT44, TRMT5, TRMT6, TRMT61A, TRMT61B,TRMU, TRNAU1AP, TRNP1, TRNT1, TRO, TROAP, TROVE2, TRPA1, TRPC1, TRPC3,TRPC4, TRPC4AP, TRPC5, TRPC50S, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3,TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPS1, TRPT1, TRPV1, TRPV2, TRPV3,TRPV4, TRPV5, TRPV6, TRRAP, TRUB1, TRUB2, TSACC, TSC1, TSC2, TSC22D1,TSC22D2, TSC22D3, TSC22D4, TSEN15, TSEN2, TSEN34, TSEN54, TSFM, TSG101,TSGA10, TSGA10IP, TSGA13, TSHB, TSHR, TSHZ1, TSHZ2, TSHZ3, TSKS, TSKU,TSLP, TSN, TSNAREl, TSNAX, TSNAX-DISC1, TSNAXIP1, TSPAN1, TSPAN10,TSPAN11, TSPAN12, TSPAN13, TSPAN14, TSPAN15, TSPAN16, TSPAN17, TSPAN18,TSPAN19, TSPAN2, TSPAN3, TSPAN31, TSPAN32, TSPAN33, TSPAN4, TSPAN5,TSPAN6, TSPAN7, TSPAN8, TSPAN9, TSPEAR, TSPO, TSPO2, TSPOAP1, TSPY1,TSPY10, TSPY2, TSPY3, TSPY4, TSPY8, TSPYL1, TSPYL2, TSPYL4, TSPYL5,TSPYL6, TSR1, TSR2, TSR3, TSSC4, TSSKlB, TSSK2, TSSK3, TSSK4, TSSK6,TST, TSTA3, TSTD1, TSTD2, TSTD3, TTBK1, TTBK2, TTC1, TTC12, TTC13,TTC14, TTC16, TTC17, TTC19, TTC21A, TTC21B, TTC22, TTC23, TTC23L, TTC24,TTC25, TTC26, TTC27, TTC28, TTC29, TTC3, TTC30A, TTC30B, TTC31, TTC32,TTC33, TTC34, TTC36, TTC37, TTC38, TTC39A, TTC39B, TTC39C, TTC4, TTC5,TTC6, TTC7A, TTC7B, TTC8, TTC9, TTC9B, TTC9C, TTF1, TTF2, TTI1, TTI2,TTK, TTL, TTLL1, TTLL10, TTLL11, TTLL12, TTLL13P, TTLL2, TTLL3, TTLL4,TTLL5, TTLL6, TTLL7, TTLL8, TTLL9, TTN, TTPA, TTPAL, TTR, TTYH1, TTYH2,TTYH3, TUB, TUBA1A, TUBAIB, TUBAIC, TUBA3C, TUBA3D, TUBA3E, TUBA4A,TUBA4B, TUBA8, TUBAL3, TUBB, TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4A,TUBB4B, TUBB6, TUBB8, TUBD1, TUBE1, TUBG1, TUBG2, TUBGCP2, TUBGCP3,TUBGCP4, TUBGCP5, TUBGCP6, TUFM, TUFT1, TULP1, TULP2, TULP3, TULP4,TUNAR, TUSC1, TUSC2, TUSC3, TUSC5, TUT1, TVP23A, TVP23B, TVP23C,TVP23C-CDRT4, TWF1, TWF2, TWISTI, TWIST2, TWISTNB, TWNK, TWSG1, TXK,TXLNA, TXLNB, TXLNG, TXN, TXN2, TXNDC11, TXNDC12, TXNDC15, TXNDC16,TXNDC17, TXNDC2, TXNDC5, TXNDC8, TXNDC9, TXNIP, TXNL1, TXNL4A, TXNL4B,TXNRD1, TXNRD2, TXNRD3, TXNRD3NB, TYK2, TYMP, TYMS, TYR, TYRO3, TYROBP,TYRP1, TYSND1, TYW1, TYW1B, TYW3, TYW5, U2AF1, U2AF1L4, U2AF1L5, U2AF2,U2SURP, UACA, UAP1, UAP1L1, UBA1, UBA2, UBA3, UBA5, UBA52, UBA6, UBA7,UBAC1, UBAC2, UBALDI, UBALD2, UBAP1, UBAPIL, UBAP2, UBAP2L, UBASH3A,UBASH3B, UBB, UBC, UBD, UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3,UBE2D4, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2F-SCLY, UBE2G1, UBE2G2,UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L5P, UBE2L6, UBE2M,UBE2N, UBE2NL, UBE20, UBE2Q1, UBE2Q2, UBE2Q2L, UBE2QL1, UBE2R2, UBE2S,UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, UBE3A, UBE3B, UBE3C, UBE3D,UBE4A, UBE4B, UBFD1, UBIAD1, UBL3, UBL4A, UBL4B, UBL5, UBL7, UBLCP1,UBN1, UBN2, UBOX5, UBP1, UBQLN1, UBQLN2, UBQLN3, UBQLN4, UBQLNL, UBR1,UBR2, UBR3, UBR4, UBR5, UBR7, UBTD1, UBTD2, UBTF, UBTFL1, UBXN1, UBXN10,UBXN11, UBXN2A, UBXN2B, UBXN4, UBXN6, UBXN7, UBXN8, UCHL1, UCHL3, UCHL5,UCK1, UCK2, UCKL1, UCMA, UCN, UCN2, UCN3, UCP1, UCP2, UCP3, UEVLD, UFC1,UFD1, UFL1, UFM1, UFSP1, UFSP2, UGCG, UGDH, UGGT1, UGGT2, UGP2, UGT1A1,UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT2A1,UGT2A2, UGT2A3, UGT2B10, UGT2B111, UGT2B15, UGT2B17, UGT2B28, UGT2B4,UGT2B7, UGT3A1, UGT3A2, UGT8, UHMK1, UHRF1, UHRF1BP1, UHRF1BP1L, UHRF2,UIMC1, ULBP1, ULBP2, ULBP3, ULK1, ULK2, ULK3, ULK4, UMAD1, UMOD, UMODL1,UMPS, UNC119, UNC119B, UNC13A, UNC13B, UNC13C, UNC13D, UNC45A, UNC45B,UNC50, UNC5A, UNC5B, UNC5C, UNC5CL, UNC5D, UNC79, UNC80, UNC93A,UNC93B1, UNCX, UNG, UNK, UNKL, UPB1, UPF1, UPF2, UPF3A, UPF3B, UPK1A,UPK1B, UPK2, UPK3A, UPK3B, UPK3BL1, UPP1, UPP2, UPRT, UQCC1, UQCC2,UQCC3, UQCR10, UQCR11, UQCRB, UQCRC1, UQCRC2, UQCRF S1, UQCRH, UQCRHL,UQCRQ, URAD, URB1, URB2, URGCP, URGCP-MRPS24, URIl, URM1, UROC1, UROD,UROS, USB1, USEl, USF1, USF2, USF3, USH1C, USH1G, USH2A, USHBP1, USMG5,USO1, USP1, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17L1,USP17L10, USP17L11, USP17L12, USP17L13, USP17L15, USP17L17, USP17L18,USP17L19, USP17L2, USP17L20, USP17L21, USP17L22, USP17L23, USP17L24,USP17L25, USP17L26, USP17L27, USP17L28, USP17L29, USP17L3, USP17L30,USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP2, USP20, USP21,USP22, USP24, USP25, USP26, USP27X, USP28, USP29, USP3, USP30, USP31,USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP4, USP40,USP41, USP42, USP43, USP44, USP45, USP46, USP47, USP48, USP49, USP5,USP50, USP51, USP53, USP54, USP6, USP6NL, USP7, USP8, USP9X, USP9Y,USPL1, UST, UTF1, UTP 11, UTP14A, UTP14C, UTP15, UTP18, UTP20, UTP23,UTP3, UTP4, UTP6, UTRN, UTS2, UTS2B, UTS2R, UTY, UVRAG, UVSSA, UXS1,UXT, VAC14, VAMP1, VAMP2, VAMP3, VAMP4, VAMP5, VAMP7, VAMP8, VANGLI,VANGL2, VAPA, VAPB, VARS, VARS2, VASH1, VASH2, VASN, VASP, VAT1, VAT1L,VAV1, VAV2, VAV3, VAX1, VAX2, VBP1, VCAM1, VCAN, VCL, VCP, VCPIP1,VCPKMT, VCX, VCX2, VCX3A, VCX3B, VCY, VCY1B, VDAC1, VDAC2, VDAC3, VDR,VEGFA, VEGFB, VEGFC, VEGFD, VENTX, VEPH1, VEZF1, VEZT, VGF, VGLL1,VGLL2, VGLL3, VGLL4, VHL, VHLL, VIL1, VILL, VIM, VIP, VIPAS39, VIPR1,VIPR2, VIRMA, VIT, VKORC1, VKORC1L1, VLDLR, VMA21, VMAC, VMO1, VMP1,VN1R1, VN1R2, VN1R4, VN1R5, VNN1, VNN2, VNN3, VOPP1, VPREB1, VPREB3,VPS11, VPS13A, VPS13B, VPS13C, VPS13D, VPS16, VPS18, VPS25, VPS26A,VPS26B, VPS28, VPS29, VPS33A, VPS33B, VPS35, VPS36, VPS37A, VPS37B,VPS37C, VPS37D, VPS39, VPS41, VPS45, VPS4A, VPS4B, VPS50, VPS51, VPS52,VPS53, VPS54, VPS72, VPS8, VPS9D1, VRK1, VRK2, VRK3, VRTN, VSIG1,VSIG10, VSIG10L, VSIG10L2, VSIG2, VSIG4, VSIG8, VSIR, VSNL1, VSTM1,VSTM2A, VSTM2B, VSTM2L, VSTM4, VSTM5, VSX1, VSX2, VTA1, VTCN1, VTI1A,VTI1B, VTN, VWA1, VWA2, VWA3A, VWA3B, VWA5A, VWA5B1, VWA5B2, VWA7, VWA8,VWC2, VWC2L, VWCE, VWDE, VWF, WAC, WAPL, WARS, WARS2, WAS, WASF1, WASF2,WASF3, WASHC1, WASHC2A, WASHC2C, WASHC3, WASHC4, WASHC5, WASL, WBP1,WBP11, WBP1L, WBP2, WBP2NL, WBP4, WDCP, WDFY1, WDFY2, WDFY3, WDFY4,WDHD1, WDPCP, WDR1, WDR11, WDR12, WDR13, WDR17, WDR18, WDR19, WDR20,WDR24, WDR25, WDR26, WDR27, WDR3, WDR31, WDR33, WDR34, WDR35, WDR36,WDR37, WDR38, WDR4, WDR41, WDR43, WDR44, WDR45, WDR45B, WDR46, WDR47,WDR48, WDR49, WDR5, WDR53, WDR54, WDR55, WDR59, WDR5B, WDR6, WDR60,WDR61, WDR62, WDR63, WDR64, WDR66, WDR7, WDR70, WDR72, WDR73, WDR74,WDR75, WDR76, WDR77, WDR78, WDR81, WDR82, WDR83, WDR83OS, WDR86, WDR87,WDR88, WDR89, WDR90, WDR91, WDR92, WDR93, WDR97, WDSUB1, WDTC1, WDYHV1,WEEl, WEE2, WFDC1, WFDC10A, WFDC10B, WFDC11, WFDC12, WFDC13, WFDC2,WFDC3, WFDC5, WFDC6, WFDC8, WFDC9, WFIKKN1, WFIKKN2, WFS1, WHAMM, WHRN,WIF1, WIPF1, WIPF2, WIPF3, WIPI1, WIPI2, WISP1, WISP2, WISP3, WIZ, WLS,WNK1, WNK2, WNK3, WNK4, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT2B,WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B,WNT9A, WNT9B, WRAP53, WRAP73, WRB, WRN, WRNIP1, WSB1, WSB2, WSCD1,WSCD2, WT1, WTAP, WTH3DI, WTIP, WWC1, WWC2, WWC3, WWOX, WWP1, WWP2,WWTR1, XAB2, XAF1, XAGE1A, XAGElB, XAGE2, XAGE3, XAGE5, XBP1, XCL1,XCL2, XCR1, XDH, XG, XIAP, XIRP1, XIRP2, XK, XKR3, XKR4, XKR5, XKR6,XKR7, XKR8, XKR9, XKRX, XPA, XPC, XPNPEP1, XPNPEP2, XPNPEP3, XPO1, XPO4,XPO5, XPO6, XPO7, XPOT, XPR1, XRCC1, XRCC2, XRCC3, XRCC4, XRCC5, XRCC6,XRN1, XRN2, XRRA1, XXYLT1, XYLB, XYLT1, XYLT2, YAE1D1, YAF2, YAP1, YARS,YARS2, YBEY, YBX1, YBX2, YBX3, YDJC, YEATS2, YEATS4, YES1, YIF1A, YIF1B,YIPF1, YIPF2, YIPF3, YIPF4, YIPF5, YIPF6, YIPF7, YJEFN3, YKT6, YLPM1,YME1L1, YOD1, YPEL1, YPEL2, YPEL3, YPEL4, YPEL5, YRDC, YTHDC1, YTHDC2,YTHDF1, YTHDF2, YTHDF3, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ, YY1,YY1AP1, YY2, Z82206.1, Z83844.1, Z84492.1, Z98749.3, Z98752.3, ZACN,ZADH2, ZAN, ZAP70, ZAR1, ZAR1L, ZBBX, ZBED1, ZBED2, ZBED3, ZBED4, ZBED5,ZBED6, ZBED6CL, ZBED8, ZBED9, ZBP1, ZBTB1, ZBTB10, ZBTB11, ZBTB12,ZBTB14, ZBTB16, ZBTB17, ZBTB18, ZBTB2, ZBTB20, ZBTB21, ZBTB22, ZBTB24,ZBTB25, ZBTB26, ZBTB3, ZBTB32, ZBTB33, ZBTB34, ZBTB37, ZBTB38, ZBTB39,ZBTB4, ZBTB40, ZBTB41, ZBTB42, ZBTB43, ZBTB44, ZBTB45, ZBTB46, ZBTB47,ZBTB48, ZBTB49, ZBTB5, ZBTB6, ZBTB7A, ZBTB7B, ZBTB7C, ZBTB8A, ZBTB8B,ZBTB8OS, ZBTB9, ZC2HC1A, ZC2HC1B, ZC2HC1C, ZC3H10, ZC3H11A, ZC3H11B,ZC3H12A, ZC3H12B, ZC3H12C, ZC3H12D, ZC3H13, ZC3H14, ZC3H15, ZC3H18,ZC3H3, ZC3H4, ZC3H6, ZC3H7A, ZC3H7B, ZC3H8, ZC3HAV1, ZC3HAV1L, ZC3HC1,ZC4H2, ZCCHC10, ZCCHC11, ZCCHCl2, ZCCHC13, ZCCHC14, ZCCHC17, ZCCHC18,ZCCHC2, ZCCHC24, ZCCHC3, ZCCHC4, ZCCHC6, ZCCHC7, ZCCHC8, ZCCHC9, ZCRB1,ZCWPW1, ZCWPW2, ZDBF2, ZDHHC1, ZDHHC11, ZDHHC11B, ZDHHC12, ZDHHC13,ZDHHC14, ZDHHC15, ZDHHC16, ZDHHC17, ZDHHC18, ZDHHC19, ZDHHC2, ZDHHC20,ZDHHC21, ZDHHC22, ZDHHC23, ZDHHC24, ZDHHC3, ZDHHC4, ZDHHC5, ZDHHC6,ZDHHC7, ZDHHC8, ZDHHC9, ZEB1, ZEB2, ZER1, ZFAND1, ZFAND2A, ZFAND2B,ZFAND3, ZFAND4, ZFAND5, ZFAND6, ZFAT, ZFC3H1, ZFHX2, ZFHX3, ZFHX4, ZFP1,ZFP14, ZFP2, ZFP28, ZFP3, ZFP30, ZFP36, ZFP36L1, ZFP36L2, ZFP37, ZFP41,ZFP42, ZFP57, ZFP62, ZFP64, ZFP69, ZFP69B, ZFP82, ZFP90, ZFP91,ZFP91-CNTF, ZFP92, ZFPL1, ZFPM1, ZFPM2, ZFR, ZFR2, ZFX, ZFY, ZFYVEl,ZFYVE16, ZFYVE19, ZFYVE21, ZFYVE26, ZFYVE27, ZFYVE28, ZFYVE9, ZG16,ZG16B, ZGLP1, ZGPAT, ZGRF1, ZHX1, ZHX1-C8orf76, ZHX2, ZHX3, ZIC1, ZIC2,ZIC3, ZIC4, ZIC5, ZIK1, ZIM2, ZIM3, ZKSCAN1, ZKSCAN2, ZKSCAN3, ZKSCAN4,ZKSCAN5, ZKSCAN7, ZKSCAN8, ZMAT1, ZMAT2, ZMAT3, ZMAT4, ZMAT5, ZMIZ1,ZMIZ2, ZMPSTE24, ZMYM1, ZMYM2, ZMYM3, ZMYM4, ZMYM5, ZMYM6, ZMYND10,ZMYND11, ZMYND12, ZMYND15, ZMYND19, ZMYND8, ZNF10, ZNF100, ZNF101,ZNF106, ZNF107, ZNF112, ZNF114, ZNF117, ZNF12, ZNF121, ZNF124, ZNF131,ZNF132, ZNF133, ZNF134, ZNF135, ZNF136, ZNF138, ZNF14, ZNF140, ZNF141,ZNF142, ZNF143, ZNF146, ZNF148, ZNF154, ZNF155, ZNF157, ZNF16, ZNF160,ZNF165, ZNF169, ZNF17, ZNF174, ZNF175, ZNF177, ZNF18, ZNF180, ZNF181,ZNF182, ZNF184, ZNF185, ZNF189, ZNF19, ZNF195, ZNF197, ZNF2, ZNF20,ZNF200, ZNF202, ZNF205, ZNF207, ZNF208, ZNF211, ZNF212, ZNF213, ZNF214,ZNF215, ZNF217, ZNF219, ZNF22, ZNF221, ZNF222, ZNF223, ZNF224, ZNF225,ZNF226, ZNF227, ZNF229, ZNF23, ZNF230, ZNF232, ZNF233, ZNF234, ZNF235,ZNF236, ZNF239, ZNF24, ZNF248, ZNF25, ZNF250, ZNF251, ZNF253, ZNF254,ZNF256, ZNF257, ZNF26, ZNF260, ZNF263, ZNF264, ZNF266, ZNF267, ZNF268,ZNF273, ZNF274, ZNF275, ZNF276, ZNF277, ZNF28, ZNF280A, ZNF280B,ZNF280C, ZNF280D, ZNF281, ZNF282, ZNF283, ZNF284, ZNF285, ZNF286A,ZNF286B, ZNF287, ZNF292, ZNF296, ZNF3, ZNF30, ZNF300, ZNF302, ZNF304,ZNF311, ZNF316, ZNF317, ZNF318, ZNF319, ZNF32, ZNF320, ZNF322, ZNF324,ZNF324B, ZNF326, ZNF329, ZNF330, ZNF331, ZNF333, ZNF334, ZNF335, ZNF337,ZNF33A, ZNF33B, ZNF34, ZNF341, ZNF343, ZNF345, ZNF346, ZNF347, ZNF35,ZNF350, ZNF354A, ZNF354B, ZNF354C, ZNF358, ZNF362, ZNF365, ZNF366,ZNF367, ZNF37A, ZNF382, ZNF383, ZNF384, ZNF385A, ZNF385B, ZNF385C,ZNF385D, ZNF391, ZNF394, ZNF395, ZNF396, ZNF397, ZNF398, ZNF404, ZNF407,ZNF408, ZNF41, ZNF410, ZNF414, ZNF415, ZNF416, ZNF417, ZNF418, ZNF419,ZNF420, ZNF423, ZNF425, ZNF426, ZNF428, ZNF429, ZNF43, ZNF430, ZNF431,ZNF432, ZNF433, ZNF436, ZNF438, ZNF439, ZNF44, ZNF440, ZNF441, ZNF442,ZNF443, ZNF444, ZNF445, ZNF446, ZNF449, ZNF45, ZNF451, ZNF454, ZNF460,ZNF461, ZNF462, ZNF467, ZNF468, ZNF469, ZNF470, ZNF471, ZNF473, ZNF474,ZNF479, ZNF48, ZNF480, ZNF483, ZNF484, ZNF485, ZNF486, ZNF487, ZNF488,ZNF490, ZNF491, ZNF492, ZNF493, ZNF496, ZNF497, ZNF500, ZNF501, ZNF502,ZNF503, ZNF506, ZNF507, ZNF510, ZNF511, ZNF512, ZNF512B, ZNF513, ZNF514,ZNF516, ZNF517, ZNF518A, ZNF518B, ZNF519, ZNF521, ZNF524, ZNF525,ZNF526, ZNF527, ZNF528, ZNF529, ZNF530, ZNF532, ZNF534, ZNF536, ZNF540,ZNF541, ZNF543, ZNF544, ZNF546, ZNF547, ZNF548, ZNF549, ZNF550, ZNF551,ZNF552, ZNF554, ZNF555, ZNF556, ZNF557, ZNF558, ZNF559, ZNF559-ZNF177,ZNF560, ZNF561, ZNF562, ZNF563, ZNF564, ZNF565, ZNF566, ZNF567, ZNF568,ZNF569, ZNF57, ZNF570, ZNF571, ZNF572, ZNF573, ZNF574, ZNF575, ZNF576,ZNF577, ZNF578, ZNF579, ZNF580, ZNF581, ZNF582, ZNF583, ZNF584, ZNF585A,ZNF585B, ZNF586, ZNF587, ZNF587B, ZNF589, ZNF592, ZNF593, ZNF594,ZNF595, ZNF596, ZNF597, ZNF598, ZNF599, ZNF600, ZNF605, ZNF606, ZNF607,ZNF608, ZNF609, ZNF610, ZNF611, ZNF613, ZNF614, ZNF615, ZNF616, ZNF618,ZNF619, ZNF620, ZNF621, ZNF622, ZNF623, ZNF624, ZNF625, ZNF625-ZNF20,ZNF626, ZNF627, ZNF628, ZNF629, ZNF630, ZNF638, ZNF639, ZNF641, ZNF644,ZNF645, ZNF646, ZNF648, ZNF649, ZNF652, ZNF653, ZNF654, ZNF655, ZNF658,ZNF66, ZNF660, ZNF662, ZNF664, ZNF665, ZNF667, ZNF668, ZNF669, ZNF670,ZNF670-ZNF695, ZNF671, ZNF672, ZNF674, ZNF675, ZNF676, ZNF677, ZNF678,ZNF679, ZNF680, ZNF681, ZNF682, ZNF683, ZNF684, ZNF687, ZNF688, ZNF689,ZNF69, ZNF691, ZNF692, ZNF695, ZNF696, ZNF697, ZNF699, ZNF7, ZNF70,ZNF700, ZNF701, ZNF703, ZNF704, ZNF705A, ZNF705B, ZNF705D, ZNF705E,ZNF705G, ZNF706, ZNF707, ZNF708, ZNF709, ZNF71, ZNF710, ZNF711, ZNF713,ZNF714, ZNF716, ZNF717, ZNF718, ZNF720, ZNF721, ZNF724, ZNF726, ZNF727,ZNF728, ZNF729, ZNF730, ZNF732, ZNF735, ZNF736, ZNF737, ZNF738, ZNF74,ZNF740, ZNF746, ZNF747, ZNF749, ZNF750, ZNF75A, ZNF75D, ZNF76, ZNF761,ZNF763, ZNF764, ZNF765, ZNF766, ZNF768, ZNF77, ZNF770, ZNF771, ZNF772,ZNF773, ZNF774, ZNF775, ZNF776, ZNF777, ZNF778, ZNF780A, ZNF780B,ZNF781, ZNF782, ZNF783, ZNF784, ZNF785, ZNF786, ZNF787, ZNF788, ZNF789,ZNF79, ZNF790, ZNF791, ZNF792, ZNF793, ZNF799, ZNF8, ZNF80, ZNF800,ZNF804A, ZNF804B, ZNF805, ZNF808, ZNF81, ZNF813, ZNF814, ZNF816,ZNF816-ZNF321P, ZNF821, ZNF823, ZNF827, ZNF829, ZNF83, ZNF830, ZNF831,ZNF835, ZNF836, ZNF837, ZNF839, ZNF84, ZNF841, ZNF843, ZNF844, ZNF845,ZNF846, ZNF85, ZNF850, ZNF852, ZNF853, ZNF860, ZNF862, ZNF865, ZNF878,ZNF879, ZNF880, ZNF883, ZNF888, ZNF891, ZNF90, ZNF91, ZNF92, ZNF93,ZNF98, ZNF99, ZNFX1, ZNHIT1, ZNHIT2, ZNHIT3, ZNHIT6, ZNRD1, ZNRF1,ZNRF2, ZNRF3, ZNRF4, ZP1, ZP2, ZP3, ZP4, ZPBP, ZPBP2, ZPLD1, ZPR1,ZRANB1, ZRANB2, ZRANB3, ZRSR1, ZRSR2, ZSCAN1, ZSCAN10, ZSCAN12, ZSCAN16,ZSCAN18, ZSCAN2, ZSCAN20, ZSCAN21, ZSCAN22, ZSCAN23, ZSCAN25, ZSCAN26,ZSCAN29, ZSCAN30, ZSCAN31, ZSCAN32, ZSCAN4, ZSCAN5A, ZSCAN5B, ZSCAN5C,ZSCAN9, ZSWIM1, ZSWIM2, ZSWIM3, ZSWIM4, ZSWIM5, ZSWIM6, ZSWIM7, ZSWIM8,ZUFSP, ZW10, ZWTLCH, ZWINT, ZXDA, ZXDB, ZXDC, ZYG11A, ZYG11B, ZYX,ZZEF1, and ZZZ3.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of an autoimmune disorder, an inflammatory disorder, or aproliferative disorder, or a disorder commonly occurring in connectionwith transplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex© and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In one embodiment, the present invention provides a compositioncomprising a provided compound and one or more additional therapeuticagents. The therapeutic agent may be administered together with aprovided compound, or may be administered prior to or followingadministration of a provided compound. Suitable therapeutic agents aredescribed in further detail below. In certain embodiments, a providedcompound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours,8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. Inother embodiments, a provided compound may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursfollowing the therapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a provided compound and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a provided compound and one or more additional therapeuticagents selected from non-steroidal anti-inflammatory drugs (NSAIDS) suchas aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarialssuch as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®),methotrexate (Rheumatrex®), gold salts such as gold thioglucose(Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®),D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®),cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine(Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such asetanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®),certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1”agents such as anakinra (Kineret®) and rilonacept (Arcalyst®),antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such asabatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab(Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof aprovided compound and one or more additional therapeutic agents selectedfrom acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) suchas aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) andmonoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatingsystemic lupus erythematosus comprising administering to a patient inneed thereof a provided compound and one or more additional therapeuticagents selected from acetaminophen, non-steroidal anti-inflammatorydrugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®)and celecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, antimalarials such ashydroxychloroquine (Plaquenil®) and chloroquine (Aralen®),cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine(Imuran®) and anticoagulants such as heparin (Calcinparine® orLiquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatingCrohn's disesase, ulcerative colitis, or inflammatory bowel diseasecomprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected frommesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such asdiphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid bindingagents such as cholestyramine, alosetron (Lotronex®), lubiprostone(Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol(MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics orantispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies,steroids, and antibiotics such as Flagyl or ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, and IgEantibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected frombeta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound and one or more additionaltherapeutic agents selected from rituximab (Rituxan®), cyclophosphamide(Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®),prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a provided compound and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereofa provided compound and a BTK inhibitor,wherein the disease is selected from inflammatory bowel disease,arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathicthrombocytopenic purpura (ITP), rheumatoid arthritis, psoriaticarthritis, osteoarthritis, Still's disease, juvenile arthritis,diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis,Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiplesclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barresyndrome, acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipidantibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmunegastritis, pernicious anemia, celiac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behcet's disease,chronic fatigue, dysautonomia, membranous glomerulonephropathy,endometriosis, interstitial cystitis, pemphigus vulgaris, bullouspemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferativedisease, rejection of transplanted organs or tissues, AcquiredImmunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes,graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma,allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferativedisorder, e.g., diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acutelymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma,multiple myeloma (also known as plasma cell myeloma), non-Hodgkin'slymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone Bcell lymphoma, nodal marginal zone B cell lymphoma, mantle celllymphoma, mediastinal (thymic) large B cell lymphoma, intravascularlarge B cell lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer,prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mastcell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer,colorectal cancer, pancreatic cancer, diseases of the bone and jointsincluding, without limitation, rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome,systemic sclerosis, osteoporosis, bone cancer, bone metastasis, athromboembolic disorder, (e.g., myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, deep venous thrombosis), inflammatory pelvicdisease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis,meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis,gastritis, enteritis, dermatitis, gingivitis, appendicitis,pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy,Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren'sdisease, tissue graft rejection, hyperacute rejection of transplantedorgans, asthma, allergic rhinitis, chronic obstructive pulmonary disease(COPD), autoimmune polyglandular disease (also known as autoimmunepolyglandular syndrome), autoimmune alopecia, pernicious anemia,glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma,vasculitis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson'sdisease, Alzheimer's disease, diabetes, septic shock, systemic lupuserythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenilearthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleraderma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a PI3K inhibitor,wherein the disease is selected from a cancer, a neurodegenativedisorder, an angiogenic disorder, a viral disease, an autoimmunedisease, an inflammatory disorder, a hormone-related disease, conditionsassociated with organ transplantation, immunodeficiency disorders, adestructive bone disorder, a proliferative disorder, an infectiousdisease, a condition associated with cell death, thrombin-inducedplatelet aggregation, chronic myelogenous leukemia (CML), chroniclymphocytic leukemia (CLL), liver disease, pathologic immune conditionsinvolving T cell activation, a cardiovascular disorder, and a CNSdisorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a PI3K inhibitor,wherein the disease is selected from benign or malignant tumor,carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minimal change nephropathy, restenosis, cardiomegaly,atherosclerosis, myocardial infarction, ischemic stroke and congestiveheart failure, Alzheimer's disease, Parkinson's disease, amyotrophiclateral sclerosis, Huntington's disease, and cerebral ischemia, andneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity and hypoxia.

In some embodiments the present invention provides a method of treatingor lessening the severity of a disease comprising administering to apatient in need thereof a provided compound and a Bcl-2 inhibitor,wherein the disease is an inflammatory disorder, an autoimmune disorder,a proliferative disorder, an endocrine disorder, a neurologicaldisorder, or a disorder associated with transplantation. In someembodiments, the disorder is a proliferative disorder, lupus, or lupusnephritis. In some embodiments, the proliferative disorder is chroniclymphocitic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease,small-cell lung cancer, non-small-cell lung cancer, myelodysplasticsyndrome, lymphoma, a hematological neoplasm, or solid tumor.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of anautoimmune disorder, an inflammatory disorder, a proliferative disorder,an endocrine disorder, a neurological disorder, or a disorder associatedwith transplantation. The exact amount required will vary from subjectto subject, depending on the species, age, and general condition of thesubject, the severity of the infection, the particular agent, its modeof administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofmodulating CRBN activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

According to another embodiment, the invention relates to a method ofbinding CRBN, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Binding CRBN (or a mutant thereof) activity in a biological sample isuseful for a variety of purposes that are known to one of skill in theart. Examples of such purposes include, but are not limited to,biological specimen storage and biological assays.

Another embodiment of the present invention relates to a method ofmodulating CRBN activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofmodulating the activity of CRBN, or a mutant thereof, in a patientcomprising the step of administering to said patient a compound of thepresent invention, or a composition comprising said compound. Accordingto certain embodiments, the invention relates to a method of reversiblyor irreversibly modulating one or more of CRBN, or a mutant thereof,activity in a patient comprising the step of administering to saidpatient a compound of the present invention, or a composition comprisingsaid compound. In other embodiments, the present invention provides amethod for treating a disorder mediated by CRBN, or a mutant thereof, ina patient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other therapeutic compounds. In some embodiments, theother therapeutic compounds are antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™ Letrozoleis marketed under the trade names Femara™ or Femar™. Aminoglutethimideis marketed under the trade name Orimeten™. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™ Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or membersof the cyclin-dependent kinase family (CDK) including staurosporinederivatives, such as midostaurin; examples of further compounds includeUCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196;isochinoline compounds; FTIs; PD184352 or QAN697 (a PI3K inhibitor) orAT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibitingthe activity of protein-tyrosine kinase inhibitors, such as compoundswhich target, decrease or inhibit the activity of protein-tyrosinekinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostinsuch as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, C1-1033, EKB-569, GW-2016, El.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Ka, PI3Ky, PI3K6, PI3KO, PI3K-C2a, PI3K-C20, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218, U.S. Pat. No. 7,514,444, WO2011090760, and U.S.Pat. No. 8,338,439, the entirety of each of which is herein incorporatedby reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, U.S. Pat. No. 7,557,210, WO2005007623, U.S. Pat.No. 7,173,015, WO2006078846, and U.S. Pat. No. 7,449,458, the entiretyof each of which is herein incorporated by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, U.S. Pat. No. 7,713,943, WO2004089925, U.S. Pat.No. 6,949,537, WO2007016176, U.S. Pat. Nos. 7,402,325, 8,138,347,WO2002088112, U.S. Pat. No. 7,071,189, WO2007084786, U.S. Pat. No.8,217,035, WO2007129161, U.S. Pat. No. 7,781,433, WO2006122806, U.S.Pat. No. 7,667,039, WO2005113554, U.S. Pat. No. 7,932,260, WO2007044729,and U.S. Pat. No. 7,989,622, the entirety of each of which is hereinincorporated by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, U.S. Pat. No. 8,185,616, WO2008109943, U.S. Pat.No. 8,486,941, WO2007053452, U.S. Pat. No. 7,528,143, WO200142246, U.S.Pat. No. 6,627,754, WO2007070514, and U.S. Pat. No. 7,598,257, theentirety of each of which is herein incorporated by reference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MM1270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase, and Bcl-2 inhibitors.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412. In some embodiments, the presentinvention provides a method of treating AML associated with an ITDand/or D835Y mutation, comprising administering a compound of thepresent invention together with a one or more FLT3 inhibitors. In someembodiments, the FLT3 inhibitors are selected from quizartinib (AC220),a staurosporine derivative (e.g. midostaurin or lestaurtinib),sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302,NMS-P948, AST-487, G-749, SB-1317, 5-209, SC-110219, AKN-028,fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3inhibitors are selected from quizartinib, midostaurin, lestaurtinib,sorafenib, and sunitinib.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene),VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Implantable devices coated with a compound of thisinvention are another embodiment of the present invention.

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fni4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTOR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin a/TNFO, TNFR2, TNFa, LTOR, Lymphotoxin al02, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-P, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO 2011/070024, US 2011/0165156, WO 2011/0107553, US 2012/0329997, WO2011/131407, US 2013/0005949, WO 2013/087699, US 2014/0336363, WO2013/119716, WO 2013/132044, US 2014/0079706) or FPA-008 (WO2011/140249, US 2011/0274683; WO 2013/169264; WO 2014/036357, US2014/0079699).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgGI, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634, US 2010/0203056), durvalumab (MED14736), BMS-936559 (WO2007/005874, US 2009/0055944), and MSB0010718C (WO 2013/079174, US2014/0341917).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO 2010/019570, US2010/0150892, WO 2014/008218, US 2014/0093511), or IMP-731 or IMP-321(WO 2008/132601, US 2010/0233183, WO 2009/044273, US 2011/0008331).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO2006/105021, US 2007/0098719, WO 2009/009116, US 2009/0136494), orMK-4166 (WO 2011/028683, US 2012/0189639).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO2009/073620, US 2011/0053941, WO 2009/132238, US 2011/0136796, WO2011/056652, US 2012/0277217, WO 2012/142237, US 2014/0066625).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO 2006/029879,U.S. Pat. No. 7,501,496).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO2011/109400, US 2013/0149236).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo*,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-lh68/GLV-lh153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TGO1 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682, the entirety of each of which isherein incorporated by reference, which discloses CAR-T cells engineeredto comprise an extracellular domain having an antigen binding domain(such as a domain that binds to CD19), fused to an intracellularsignaling domain of the T cell antigen receptor complex zeta chain (suchas CD3 zeta). When expressed in the T cell, the CAR is able to redirectantigen recognition based on the antigen binding specificity. In thecase of CD19, the antigen is expressed on malignant B cells. Over 200clinical trials are currently in progress employing CAR-T in a widerange of indications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+(Th17) and CD8+(Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCTO2124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams ET. AL., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by refenrece in itsentirety. In some embodimetne, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams ET. AL. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncoloby target selected from those listed in Table 2 of Jerry L.Adams ET. AL. In some embodiments, an immuno-oncology agent is a smallmolecule agent selectd from those listed in Table 2 of Jerry L. AdamsET. AL.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by refenrece in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the conten of which is incorporated herein by referencein its entirety. In some embodiments, an immuno-oncology agent is abispecific T cell engager (BiTE®) antibody construct. In someembodimens, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodimens, a bispecificT cell engager (BiTE®) antibody construct is an EGFR/CD3 bispecificantibody construct. In some embodimens, a bispecific T cell engager(BiTE®) antibody construct activates T cells. In some embodimens, abispecific T cell engager (BiTE®) antibody construct activates T cells,which release cytokines inducing upregulation of intercellular adhesionmolecule 1 (ICAM-1) and FAS on bystander cells. In some embodimens, abispecific T cell engager (BiTE®) antibody construct activates T cellswhich result in induced bystander cell lysis. In some embodiments, thebystander cells are in solid tumors. In some embodiments, the bystandercells being lysed are in proximity to the BiTE®-acticvated T cells. Insome embodiment, the bystander cells comprises tumor-associated antigen(TAA) negatgive cancer cells. In some embodiment, the bystander cellscomprise EGFR-negative cancer cells. In some embodiments, animmuno-oncology agent is an antibody which blocks the PD-L1/PD1 axisand/or CTLA4. In some embodiments, an immuno-oncology agent is anex-vivo expanded tumor-infiltrating T cell. In some embodiments, animmuno-oncology agent is a bispecific antibody construct or chimericantigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺ (αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1; MEDI4736), MK-3475(PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody),BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgGI anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgGI Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KTR) inhibitors. KTR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgGI, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION General Synthetic Methods

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

All reactions are carried out under nitrogen or argon unless otherwisestated.

Proton NMR (¹H NMR) is conducted in deuterated solvent. In certaincompounds disclosed herein, one or more ¹H shifts overlap with residualproteo solvent signals; these signals have not been reported in theexperimental provided hereinafter.

TABLE 2 Analytical instruments LCMS Shimadzu UFLC MS: LCMS-2020 AgilentTechnologies 1200 series MS: Agilent Technologies 6110 AgilentTechnologies 1200 series MS: LC/MSD VL NMR BRUKER AVANCE III/400;Frequency (MHz) 400.13; Nucleus: 1H; Number of Transients: 8 Prep-Gilson GX-281 systems: instruments GX-A, GX-B, GX-C, HPLC GX-D, GX-E,GX-F, GX-G and GX-H GCMS SHIMADZU GCMS-QP2010 Ultra Analytical AgilentTechnologies 1290 Infinity cSFC Prep-cSFC Waters SFC Prep 80

For acidic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH+] and equipped with ChromolithFlash RP-18e 25*2.0 mm, eluting with 0.0375 vol % TFA in water (solventA) and 0.01875 vol % TFA in acetonitrile (solvent B). Other LCMS wasrecorded on an Agilent 1290 Infinity RRLC attached with Agilent 6120Mass detector. The column used was BEH C18 50*2.1 mm, 1.7 micron. Columnflow was 0.55 ml/min and mobile phase were used (A) 2 mM AmmoniumAcetate in 0.1% Formic Acid in Water and (B) 0.1% Formic Acid inAcetonitrile.

For basic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS 2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH+] and equipped with Xbridge C18,2.1X50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C182.1X30 mm columns packed with 5 mm C18-coated silica, eluting with 0.05vol % NH₃H₂O in water (solvent A) and acetonitrile (solvent B).

HPLC Analytical Method: HPLC was carried out on X Bridge C18 150*4.6 mm,5 micron. Column flow was 1.0 ml/min and mobile phase were used (A) 0.1%Ammonia in water and (B) 0.1% Ammonia in Acetonitrile.

Prep HPLC Analytical Method: The compound was purified on ShimadzuLC-20AP and UV detector. The column used was X-BRIDGE C18 (250*19)mm, 5.Column flow was 16.0 ml/min. Mobile phase were used (A) 0.1% Formic Acidin Water and (B) Acetonitrile Basic method used (A) 5 mM ammoniumbicarbonate and 0.1% NH3 in Water and (B) Acetonitrile or (A) 0.1%Ammonium Hydroxide in Water and (B) Acetonitrile. The UV spectra wererecorded at 202 nm & 254 nm.

NMR Method: The 1H NMR spectra were recorded on a Bruker Ultra ShieldAdvance 400 MHz/5 mm Probe (BBFO). The chemical shifts are reported inpart-per-million.

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

INTERMEDIATES 6-Bromo-9H-pyrido[2,3-b]indole (Intermediate A)

To a stirred solution of 9H-pyrido[2,3-b]indole (3 g, 17.9 mmol) in DCM(50 mL) was added dropwise of Br₂ (3.4 g, 21.4 mmol) at 0° C. To themixture was added aq. NaHCO₃ (100 mL), extracted with EA (200 mL). Theorganic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, concentrated to give product 6-bromo-9H-pyrido[2,3-b]indole(2.7 g, 61% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02(s, 1H), 8.60 (dd, J=1.2 Hz, J=7.6 Hz, 1H), 8.48-8.44 (m, 2H), 7.60-7.58(m, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.26 (dd, J=4.8 Hz, J=7.6 Hz, 1H).LC/MS (ESI, m/z): [M+1]⁺=247.8.

tert-Butyl methyl(3-(prop-2-yn-1-yloxy)propyl)carbamate (Intermediate B)

To a solution of tert-butyl (3-hydroxypropyl)(methyl)carbamate (2 g,10.6 mmol) in DCM (30 mL) was added aq. NaOH (40%, 20 mL),3-bromoprop-1-yne (1.9 g, 15.9 mmol) and TBAHS (180 mg, 0.530 mmol) atrt. The mixture was stirred for 3 h at rt. To the mixture was added H₂O(100 mL), extracted with DCM (100 mL). The organic layer was washed withbrine (50 mL), dried over Na₂SO₄, filtered, concentrated and purified bycolumn (PE/EA=20/1 to 10/1 to 4/1) to give product tert-butylmethyl(3-(prop-2-yn-1-yloxy)propyl)carbamate (1.4 g, 58% yield) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.14 (d, J=6.4 Hz, 2H), 3.53 (t,J=6.4 Hz, 2H), 3.29 (t, J=6.8 Hz, 2H), 2.86 (s, 3H), 2.42 (t, J=2.4 Hz,1H), 1.85-1.78 (m, 2H), 1.46 (s, 9H). LC/MS (ESI, m/z): [M+1]⁺=227.9

tert-Butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (IntermediateC)

To a solution of tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate (2 g,9.74 mmol) in DCM (30 mL) was added aq. NaOH (40%, 20 mL),3-bromoprop-1-yne (1.7 g, 14.6 mmol) and TBAHS (0.17 g, 0.487 mmol) atrt. The mixture was stirred at room temperature for 3 h. To the mixturewas added H₂O (100 mL), extracted with DCM (100 mL). The organic layerwas washed with brine (50 mL), dried over Na₂SO₄, filtered, concentratedand purified by column (PE/EA=20/1 to 10/1 to 4/1) to give producttert-butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (1.6 g, 68%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.98 (br s, 1H), 4.21(d, J=2.0 Hz, 2H), 3.71-3.69 (m, 2H), 3.66-3.63 (m, 2H), 3.55 (t, J=5.2Hz, 2H), 3.34-3.30 (m, 2H), 2.45 (t, J=2.4 Hz, 1H), 1.45 (s, 9H); LC/MS(ESI, m/z): [M+1]⁺=243.9.

2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethanol (Intermediate D)

To a mixture of Ag₂O (12.4 g, 100 mmol) and KI (4.42 g, 26.64 mmol) inDCM (200 mL) was added 2,2′-(ethane-1,2-diylbis(oxy))diethanol (10 g,66.6 mmol) dropwise at room temperature. Then BnBr (12.5 g, 73.26 mmol)was added dropwise into the mixture over 10 min. After addition, themixture was stirred at room temperature for 2 h. The reaction mixturewas filtered. The combined filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethanol (7 g, 43.8%) as acolorless oil. LC/MS (ESI, m/z): [M+1]⁺=241.0.

9H-Pyrido[2,3-b]indole-6-carbonitrile (Intermediate E)

Step 1: 4-((3-bromopyridin-2-yl)amino)benzonitrile

A mixture of 3-bromopyridin-2-amine (10 g, 57.8 mmol),4-iodobenzonitrile (13.2 g, 57.8 mmol), palladium acetate (0.65 g, 2.89mmol), xantphos (1.67 g, 2.89 mmol) and caesium carbonate (28.2 g, 86.7mmol) in anisole was degassed with nitrogen, heated to 130° C. andstirred for 17 hours under nitrogen atmosphere. The reaction was cooledto r.t and filtered. The filtrate was concentrated in vacuum. Theresidue was purified by column chromatography (Petroleumether/EtOAc=6:1) to give 4-((3-bromopyridin-2-yl)amino)benzonitrile (9.7g, 61.3% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=275.1.

Step 2: 9H-pyrido[2,3-b]indole-6-carbonitrile

A mixture of 4-((3-bromopyridin-2-yl)amino)benzonitrile (2 g, 7.30mmol), palladium acetate (0.16 g, 0.73 mmol), DUB (2.2 g, 14.6 mmol) andDCHPB (0.51 g, 1.46 mmol) in DMA (10 mL) was degassed with nitrogen,heated to 170° C. and stirred for 2 hours under microwave condition. Thereaction was cooled to r.t and filtered. The filtrate was purified viareverse phase column chromatography (CH₃CN/H₂O=5%-80%) to give9H-pyrido[2,3-b]indole-6-carbonitrile (0.75 g, 53.5% yield) as a whitesolid. LC/MS (ESI, m/z): [M+1]⁺=194.3.

4-Bromo-9H-pyrido[2,3-b]indole (Intermediate F)

Step 1: 9H-pyrido[2,3-b]indole 1-oxide

To a stirred solution of 9H-pyrido[2,3-b]indole (100 mg, 0.595 mmol) inHOAc (2 mL) was added H₂O₂(30%, 472 mg, 4.17 mmol) dropwise. The mixturewas heated to 110° C. and refluxed for 4 h. The mixture was concentratedunder reduced pressure to remove the solvent. The residue was adjust topH=8 with aq. K₂CO₃. The result solution was stirred for overnight atrt. To the mixture was added H₂O (20 mL), extracted with EA (50 mL). Theorganic layer was washed with brine (30 mL), dried over Na₂SO₄,filtered, concentrated to give product 9H-pyrido[2,3-b]indole 1-oxide(80 mg, 73% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 12.58 (brs, 1H), 8.35 (dd, J=0.8 Hz, J=6.4 Hz, 1H), 8.22-8.17 (m, 2H), 7.58-7.51(m, 2H), 7.32-7.28 (m, 1H), 7.23 (dd, J=6.4 Hz, J=7.6 Hz, 1H).

Step 2: 4-bromo-9H-pyrido[2,3-b]indole

To a stirred solution of 9H-pyrido[2,3-b]indole 1-oxide (1 g, 5.43 mmol)in DMF (30 mL) was added POBr₃ (4.68 g, 16.3 mmol) at 0° C. under N₂.The mixture was stirred at room temperature overnight. To the mixturewas added H₂O (100 mL), extracted with EA (200 mL). The organic layerwas washed with brine (100 mL), dried over Na₂SO₄, filtered,concentrated to give product 4-bromo-9H-pyrido[2,3-b]indole (700 mg, 54%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ. 9.28 (br s, 1H),8.61 (d, J=8.0 Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.59-7.52 (m, 2H), 7.40(d, J=5.4 Hz, 1H), 7.39-7.35 (m, 1H).

5-Bromo-9H-pyrido[2,3-b]indole (Intermediate G)

Step 1: N-(3-bromophenyl)-3-nitropyridin-2-amine

To a solution of 2-chloro-3-nitro-pyridine (5.00 g, 315 mmol) and3-bromoaniline (5.97 g, 34.7 mmol) in dioxane (40 mL) was added DIEA(12.2 g, 94.6 mmol). The reaction mixture was stirred at 115° C. for 2days. On completion, the mixture was concentrated in vacuo. The residuewas purified by silica gel chromatography to giveN-(3-bromophenyl)-3-nitropyridin-2-amine (8.00 g, 86% yield) as a redsolid. LC/MS (ESI, m/z): [M+1]⁺=295.1.

Step 2: N²-(3-bromophenyl)pyridine-2,3-diamine

To a solution of N-(3-bromophenyl)-3-nitropyridin-2-amine (5.00 g, 17.0mmol) and NH₄Cl (9.09 g, 170 mmol) in a mixed solvent of H₂O (80 mL) andEtOH (80 mL) was added Fe (9.49 g, 170 mmol). The reaction mixture wasstirred at 80° C. for 1 hr. On completion, the mixture was diluted withwater (80 mL) and extracted with EA (2×80 mL). The organic layers werewashed with brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give N²-(3-bromophenyl)pyridine-2,3-diamine(4.00 g, 89% yield) as a brown solid. The crude was used for the nextstep directly without further purification. LC/MS (ESI, m/z):[M+1]⁺=265.1.

Step 3: 3-(3-bromophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine

To a solution of N2-(3-bromophenyl)pyridine-2,3-diamine (4.00 g, 15.1mmol) in a mixed solvent of HOAc (25 mL) and DCM (25 mL) was added asolution of NaNO₂ (1.36 g, 19.7 mmol) in H₂O (15 mL) dropwise at 0° C.The reaction mixture was stirred at 25° C. for 30 minutes. Oncompletion, the mixture was diluted with water (50 mL), extracted withDCM (2×50 mL). The organic layer was washed with brine (2×50 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give3-(3-bromophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (4.10 g, 98% yield)as a brown solid. The crude was used for the next step directly withoutfurther purification. LC/MS (ESI, m/z): [M+1]⁺=276.1.

Step 4: 5-bromo-9H-pyrido[2,3-b]indole

A mixture of 3-(3-bromophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (3.60g, 13.1 mmol) in PPA (20 mL) was heated at 170° C. for 3 hr. Oncompletion, the mixture was poured into the ice water (200 mL), stirredfor 1 hrs, filtered. The solid cake was washed with ice-water and driedto give 5-bromo-9H-pyrido[2,3-b]indole (3.2 g, quant.). The crude wasused next step without further purification.

Step 5: tert-butyl 5-bromo-9H-pyrido[2,3-b]indole-9-carboxylate

A mixture of 5-bromo-9H-pyrido[2,3-b]indole (10.0 g, 40.0 mmol) inTHF/H₂O (100 mL/100 mL) was added Boc₂O (17.4 g, 80.0 mmol) and NaOH(4.8 g, 120.0 mmol). The mixture was stirred at r.t for 3 hr. Oncompletion, the mixture was poured into the water (200 mL), extractedwith EA (2×100 mL). The organic layer was washed with brine (2×100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by column chromatography to give tert-butyl5-bromo-9H-pyrido[2,3-b]indole-9-carboxylate (4.10 g, 7% yield for twosteps) as a brown solid. LC/MS (ESI, m/z): [M+1]+=348.1.

Step 6: 5-bromo-9H-pyrido[2,3-b]indole

A mixture of tert-butyl 5-bromo-9H-pyrido[2,3-b]indole-9-carboxylate(9.0 g, 25.9 mmol) in DCM (20 mL) was added TFA (15 mL). The mixture wasstirred at r.t for 16 h. On completion, the mixture was concentrated togive 5-bromo-9H-pyrido[2,3-b]indole (6.0 g, 94% yield) as a brown solid.LC/MS (ESI, m/z): [M+1]+=248.1.

2-Chloro-9H-pyrido[2,3-b]indole (Intermediate H)

Step 1: N-(2-iodophenyl)acetamide

A mixture of 2-iodoaniline (2.2 g, 10.0 mmol), Ac₂O (1.2 g, 12.0 mmol)and Et₃N (2.2 g, 22 mmol) in DCM was degassed with nitrogen, the mixturewas stirred for 16 hours at r.t. The reaction was concentrated in vacuo.The residue was purified by column chromatography to giveN-(2-iodophenyl)acetamide (1.6 g, 58% yield) as a white solid. LC/MS(ESI, m/z): [M+1]⁺=262.1.

Step 2: N-(2-(2,6-dichloropyridin-3-yl)phenyl)acetamide

A mixture of N-(2-iodophenyl)acetamide (261 mg, 1.0 mmol),(2,6-dichloropyridin-3-yl)boronic acid (230 mg, 1.2 mmol), palladiumacetate (11 mg, 0.05 mmol), PPh₃ (26 mg, 0.1 mmol) and Et₃N (303 mg, 3.0mmol) in DMF was degassed with nitrogen, heated to 100° C. and stirredfor 16 hours. The mixture was cooled to r.t, diluted with water andextracted with EA. The combined organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The residue was purified by column chromatography to giveN-(2-(2,6-dichloropyridin-3-yl)phenyl)acetamide (180 mg, 69% yield) as awhite solid. LC/MS (ESI, m/z): [M+1]⁺=282.1

Step 3: 2-chloro-9H-pyrido[2,3-b]indole

A mixture of N-(2-(2,6-dichloropyridin-3-yl)phenyl)acetamide (180 mg,0.64 mmol), K₂CO₃ (265 mg, 1.92 mmol) and 60% NaH (52 mg, 1.28 mmol) inDMF was degassed with nitrogen, heated to 100° C. and stirred for 4hours. The reaction was cooled to r.t, diluted with water and extractedwith EA. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography to give2-chloro-9H-pyrido[2,3-b]indole (50 mg, 43% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 8.56 (d, J=8.0 Hz, 1H), 8.18 (d,J=8.0, 1H), 7.56-7.44 (m, 2H), 7.31-7.22 (m, 2H). LC/MS (ESI, m/z):[M+1]⁺=203.8.

2-Fluoro-9H-pyrido[2,3-b]indole (Intermediate I) andN-(4-methoxybenzyl)-9H-pyrido[2,3-b]indol-2-amine (Intermediate J)

Step 1: 2-fluoro-5-(2-nitrophenyl)pyridine

A mixture of 1-bromo-2-nitrobenzene (3 g, 14.85 mmol),(6-fluoropyridin-3-yl)boronic acid (2.511 g, 17.82 mmol), Pd(PPh₃)₄(857mg, 0.7425 mmol) and Na₂CO₃ (3.94 g, 37.125 mmol) in dioxane (30 mL) andH₂O (5 mL) was heated to 110° C. and stirred overnight under nitrogenatmosphere. The reaction mixture was cooled to r.t and concentrated invacuum. The residue was diluted with water and extract with EtOAc. Thecombined organic layers was washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel column chromatography (PE/EA=4:1) to give2-fluoro-5-(2-nitrophenyl)pyridine (2.2 g, 68.2%) as a yellow solid.LC/MS (ESI, m/z): [M+1]⁺=219.2

Step 2: 2-fluoro-9H-pyrido[2,3-b]indole

To a mixture of 2-fluoro-5-(2-nitrophenyl)pyridine (2.2 g, 10.0 mmol)and 1,10-phenanthroline (63 mg, 0.35 mmol) in DMF (10 mL) was addedPd(OAc)₂ (11.2 mg, 0.05 mmol). The reactor system was sealed and purgedthree times with nitrogen followed by carbon monoxide. The system waspressurized with carbon monoxide (100 psi) and heated at 140° C. for 18h. The mixture was cooled to r.t, diluted with water and extracted withEA. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography (PE/EA=1:1) to give2-fluoro-9H-pyrido[2,3-b]indole (1.2 g, 64.5%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 12.01 (br. s., 1H), 8.66 (t, J=8.1 Hz, 1H), 8.15(d, J=7.7 Hz, 1H), 7.52 (d, J=8.13 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.26(t, J=7.7 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H). LC/MS (ESI, m/z):[M+1]⁺=186.9.

Step 3: N-(4-methoxybenzyl)-9H-pyrido[2,3-b]indol-2-amine

A mixture of 2-fluoro-9H-pyrido[2,3-b]indole (800 mg, 4.3 mmol) andPMB-NH₂(5 mL) was heated to 180° C. under nitrogen atmosphere inmicrowave irradiation for 2 h. The reaction mixture was cooled to roomtemperature and purified by silica gel column chromatography (PE/EA=4:1)to give N-(4-methoxybenzyl)-9H-pyrido[2,3-b]indol-2-amine (1.0 g, 76.7%)as a white solid. LC/MS (ESI, m/z): [M+1]⁺=304.1.

2-Methoxy-9H-pyrido[2,3-b]indole (Intermediate K)

Step 1: 2-methoxy-5-(2-nitrophenyl)pyridine

A mixture of 1-bromo-2-nitrobenzene (3.0 g, 14.8 mmol),(6-methoxypyridin-3-yl)boronic acid (2.7 g, 17.8 mmol) N₂CO₃ (4.7 g,44.5 mmol) and Tetrakis(triphenylphosphine)palladium(1.4 g, 1.2 mmol) in1,4-dioxane was degassed with nitrogen, heated to 110° C. and stirredfor 1.5 hours under nitrogen atmosphere and microwave. The reaction wascooled to r.t, filtered and concentrated in vacuo. The residue wasdiluted with water, extracted with EA. The combined organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyto give 2-methoxy-5-(2-nitrophenyl)pyridine (590 mg, 17% yield) as ayellow solid. LC/MS (ESI, m/z): [M+1]⁺=231.2.

Step 2: 2-methoxy-9H-pyrido[2,3-b]indole

A solution of 2-methoxy-5-(2-nitrophenyl)pyridine (590 mg, 2.5 mmol) inanhydrous tetrahydrofuran (10 mL) was sealed and purged three times withnitrogen. Phenyl magnesium bromide (10 ml, 10 mmol) was slowly added tothe above solution in 10 mins at 0° C. During this period, the internaltemperature was closely monitored and kept under 3° C. After addition,the reaction mixture was stirred at 0° C. for 30 minutes. The reactionwas quenched by sat. aq. ammonium chloride, extracted with EA. Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography to give2-methoxy-9H-pyrido[2,3-b]indole (100 mg, 20% yield) as a white solid.LC/MS (ESI, m/z): [M+1]⁺=199.2

2-(Trifluoromethyl)-9H-pyrido[2,3-b]indole (Intermediate L)

Step 1: 3-bromo-2-chloro-6-(trifluoromethyl)pyridine

A mixture of 2-chloro-6-(trifluoromethyl)pyridin-3-amine (196 mg, 1.0mmol), CuBr (446 mg, 2.0 mmol) and t-BuNO₂ (206 mg, 2.0 mmol) in CH₃CNwas degassed with nitrogen, the mixture was stirred at r.t for 2 hours.The mixture was diluted with water extracted with EA. The combinedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography to give3-bromo-2-chloro-6-(trifluoromethyl)pyridine (182 mg, 70% yield) as ayellow solid. LC/MS (ESI, m/z): [M+1]⁺=261.1.

Step 2: 2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)aniline

A mixture of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (258 mg, 1.0mmol), (2-aminophenyl)boronic acid (163 mg, 1.2 mmol), Pd(PPh₃)₄(58 mg,0.05 mmol) and Na₂CO₃ (212 mg, 2.0 mmol) in DMF/H₂O (5 mL/0.5 mL) wasdegassed with nitrogen, heated to 100° C. and stirred for 16 hours. Themixture was cooled to r.t, diluted with water and extracted with EA. Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography to give2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)aniline (180 mg, 66% yield)as a white solid. LC/MS (ESI, m/z): [M+1]⁺=273.1.

Step 3: 2-(trifluoromethyl)-9H-pyrido[2,3-b]indole

A mixture of 2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)aniline (120mg, 0.44 mmol), K₂CO₃ (18 mg, 1.32 mmol) and 60% NaH (40 mg, 1.32 mmol)in DMF was degassed with nitrogen, heated to 100° C. and stirred for 4hours. The reaction was cooled to r.t, diluted with water and extractedwith EA. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography to give2-(trifluoromethyl)-9H-pyrido[2,3-b]indole (42 mg, 40% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 8.78 (d, J=7.9Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.58-7.56 (m,2H), 7.38-7.14 (m, 1H). LC/MS (ESI, m/z): [M+1]⁺=237.1.

3-(7-Bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (IntermediateM)

Step 1: 3-bromo-N-(3-nitrophenyl)pyridin-2-amine

To a mixture of 3-bromopyridin-2-amine (5 g, 28.9 mmol),1-iodo-3-nitrobenzene (7.2 g, 28.9 mmol), xanphos (1.07 g, 2.89 mmol),Cs₂CO₃(18.9 g, 57.8 mmol) in DMF (50 mL) was added Pd(OAc)₂ (323.7 mg,1.44 mmol). The mixture was degrassed with N₂ and stirred at 130° C.overnight. The reaction mixture was cooled to room temperature, pouredinto water, and extracted with EtOAc(3×200 mL). The combined organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography eluting with EA/PE=20% to give3-bromo-N-(3-nitrophenyl)pyridin-2-amine (5.6 g, 65.7%) as a lightyellow solid. LC/MS (ESI, m/z): [M+1]⁺=294.0, 296.0.

Step 2: 7-nitro-9H-pyrido[2,3-b]indole

To a mixture of 3-bromo-N-(3-nitrophenyl)pyridin-2-amine (4 g, 6.78mmol), DCPHB (474 mg, 1.356 mmol), DBU (4.12 g, 27.12 mmol) in DMA (12mL) was added Pd(OAc)₂ (152 mg, 0.678 mmol). The mixture was degrassedwith N₂ and stirred at 170° C. for 1h. The reaction mixture was cooledto room temperature, poured into water and extracted with EtOAc(3×50mL). The combined organic layer was washed with water and brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with EA/PE=1:1 togive 7-nitro-9H-pyrido[2,3-b]indole (1 g, 34.4%) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.72 (dd, J=7.75, 1.25Hz, 1H), 8.59 (dd, J=4.75, 1.50 Hz, 1H), 8.44 (d, J=8.63 Hz, 1H), 8.33(d, J=2.00 Hz, 1H), 8.12 (dd, J=8.63, 2.13 Hz, 1H), 7.35 (dd, J=7.75,4.75 Hz, 1H); LC/MS (ESI, m/z): [M+1]⁺=214.1.

Step 3:1-(4-methoxybenzyl)-3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of 7-nitro-9H-pyrido[2,3-b]indole (910 mg, 4.272 mmol) inTHE (10 mL) and DMF (2 mL) was added t-BuOK (718 mg, 6.41 mmol) at 0° C.under nitrogen atmosphere. After addition, the mixture was stirred at 0°C.-5° C. for 1 h. Then the 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yltrifluoromethanesulfonate (2.44 g, 6.41 mmol) in THF (10 mL) was addeddropwise at 0° C.-5° C. over 20 min. After addition, the mixture wasstirred at 0° C.-5° C. for additional 1 h. The reaction mixture wasquenched by water and extract with EtOAc (3×20 mL). The combined organiclayer were washed with water and brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced. The residue wastriturated with EtOAc and filtered to give1-(4-methoxybenzyl)-3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(1.3 g, 68.6%) as a yellow solid. The crude was used directly in thenext step without further purification. LC/MS (ESI, m/z): [M+1]⁺=445.2.

Step 4: 3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of1-(4-methoxybenzyl)-3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(1.7 g, 3.83 mmol) in CH₃CN (20 mL) was added CAN (10.5 g, 19.15 mmol)in water (5 mL) at 0° C. dropwise. After addition, the mixture wasstirred at room temperature overnight. The mixture was poured into water(50 mL) and extract with EtOAc (3×50 mL). The combined organic layerswas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was triturated with EtOAc andfiltered to give3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (850 mg,68.5%) as a light yellow solid. LC/MS (ESI, m/z): [M+1]⁺=325.2.

Step 5: 3-(7-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (850 mg, 2.62mmol) in EtOAc (5 mL) was added 10% palladium on activated carbon (270mg, 0.262 mmol). The mixture was hydrogened at room temperatureovernight. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was dried to give3-(7-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (764 mg, 99%)as a white solid, which was used directly in the next step withoutfurther purification. LC/MS (ESI, m/z): [M+1]⁺=295.2.

Step 6: 3-(7-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-(7-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (661 mg, 2.26mmol) in 40% HBr solution (5 mL) was added NaNO₂(156 mg, 2.26 mmol) at0° C. After addition, the mixture was stirred at 0° C. for 30 min. Thenthe above solution was added dropwise into a solution of CuBr (972 mg,6.78 mmol) in 40% HBr solution (5 mL). The mixture was stirred at roomtemperature for 2 h. Then the mixture was poured into water (50 mL). Themixture was basified to pH 8 by sat. aq. NaHCO₃ and extracted with EtOAc(3×50 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by prep-HPLC to give3-(7-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (382 mg,47.1%) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=358.1, 360.1.

1-Methoxy-9H-pyrido[3,4-b]indole (Intermediate N)

Step 1: 2-methoxy-4-(2-nitrophenyl)pyridine

A mixture of 1-bromo-2-nitrobenzene (1.1 g, 5.45 mmol),(2-methoxypyridin-4-yl)boronic acid (1.0 g, 6.54 mmol),1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.44 g, 0.54 mmol) and potassium carbonate (1.5g, 10.9 mmol) in acetonitrile (20 mL) and water (5 mL) was degassed withnitrogen, heated to 80° C. and stirred for 2 hours under nitrogenatmosphere. The reaction was cooled to r.t and filtered. The filtratewas diluted with water, extracted with EA. The combined organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatography(Petroleum ether/EtOAc=1:1) to give 2-methoxy-4-(2-nitrophenyl)pyridine(1.1 g, 88.0% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=231.1.

Step 2: 1-methoxy-9H-pyrido[3,4-b]indole

A solution of 2-methoxy-4-(2-nitrophenyl)pyridine (1.1 g, 4.78 mmol) inDMF (15 mL) was added Pd(OAc)₂ (5.4 mg, 0.02 mmol) and1,10-phenanthroline (30.1 mg, 0.17 mmol). The reactor system was sealedand purged three times with nitrogen followed by carbon monoxide. Thesystem was pressurized with carbon monoxide (100 psi) and heated at 140°C. for 17 h. The mixture was cooled to rt, diluted with water andextracted with EA. The combined organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The residue was purified by column chromatography (Petroleumether/EtOAc=1:1) to give 1-methoxy-9H-pyrido[3,4-b]indole (0.75 g, 78.9%yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=199.1.

9H-Pyrido[3,4-b]indole (Intermediate O)

Step 1: 4-bromo-N-phenylpyridin-3-amine

A mixture of 4-bromopyridin-3-amine (865 mg, 5.0 mmol), iodobenzene(1.02 mg, 5.0 mmol), xantphos (288 mg, 0.5 mmol) and Cs₂CO₃ (2.46 g, 7.5mmol) in DMF was degassed with nitrogen, heated to 130° C. and stirredfor 16 hours under microwave condition. The reaction was cooled to r.tand filtered. The filtrate was diluted with water, extracted with EA.The combined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography to give4-bromo-N-phenylpyridin-3-amine (311 mg, 25% yield) as a yellow solid.LC/MS (ESI, m/z): [M+1]⁺=250.1.

Step 2: 9H-pyrido[3,4-b]indole

A mixture of 4-bromo-N-phenylpyridin-3-amine (500 mg, 2.0 mmol),palladium acetate (89 mg, 0.4 mmol) and K₃PO₄ (1.27 g, 6.0 mmol) in DMA(10 mL) was degassed with nitrogen, heated to 170° C. and stirred for 2hours under microwave condition. The reaction was cooled to r.t andfiltered. The filtrate was purified via reverse phase columnchromatography (CH₃CN/H₂O=5%-80%) to give 9H-pyrido[3,4-b]indole (120mg, 28% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (s,1H), 9.27 (s, 1H), 8.74 (d, J=6.1 Hz, 1H), 8.58 (d, J=6.1 Hz, 1H), 8.51(d, J=8.0 Hz, 1H), 7.82-7.76 (m, 2H), 7.55-7.27 (m, 1H). LC/MS (ESI,m/z): [M+1]⁺=169.2.

5H-Pyrido[4,3-b]indole (Intermediate P)

Step 1: 3-bromo-N-phenylpyridin-4-amine

A mixture of 3-bromopyridin-4-amine (1.1 g, 6.36 mmol), iodobenzene (1.3g, 6.36 mmol), palladium acetate (0.14 g, 0.64 mmol), xantphos (0.37 g,0.64 mmol) and caesium carbonate (4.1 g, 12.7 mmol) in DMF was degassedwith nitrogen, heated to 130° C. and stirred for 17 hours under nitrogenatmosphere. The reaction was cooled to r.t and filtered. The filtratewas diluted with water and extracted with EA. The combined organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatography(Petroleum ether/EtOAc=6:1) to give 3-bromo-N-phenylpyridin-4-amine(0.87 g, 55.0% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=250.1.

Step 2: 5H-pyrido[4,3-b]indole

A mixture of 3-bromo-N-phenylpyridin-4-amine (0.87 g, 3.49 mmol),palladium acetate (78.4 mg, 0.35 mmol), DUB (1.1 g, 6.99 mmol) and DCHPB(0.24 g, 0.70 mmol) in DMA (10 mL) was degassed with nitrogen, heated to170° C. and stirred for 2 hours under microwave condition. The reactionwas cooled to r.t and filtered. The filtrate was purified via reversephase column chromatography (CH₃CN/H₂O=5%-80%) to give5H-pyrido[4,3-b]indole (0.30 g, 51.1% yield) as a yellow solid. LC/MS(ESI, m/z): [M+1]⁺=169.3.

3,5-Dibromopyridin-2-amine (Intermediate Q)

A mixture of 3,5-dibromopyridin-2-amine (5.0 g, 19.8 mmol),cyclohexanone (3.9 g, 39.7 mmol), DABCO (6.6 g, 59.5 mmol) and Pd(OAc)₂(440 mg, 2.0 mmol) in DMF was degassed with nitrogen, heated to 140° C.and stirred for 16 hours under nitrogen atmosphere. The reaction wascooled to r.t, filtered and concentrated in vacuo. The residue wasdiluted with water, extracted with EA. The combined organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified via reverse phase columnchromatography (CH₃CN/H₂O=5%-80%) to give6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (210 mg, 14% yield) as a whitesolid. LC/MS (ESI, m/z): [M+1]⁺=173.2.

6-Benzyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine(Intermediate R)

To a mixture of 1-benzylpiperidin-4-one (6.18 g, 27.5 mmol) and2-hydrazinylpyridine (3 g, 27.5 mmol) in EtOH (70 mL) was added AcOH (2mL). The mixture was heated to 100° C. and stirred for 2 h. Then thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The residue was diluted with 2M NaOH (aq) andextracted with DCM. The combined organic layers were concentrated underreduced pressure. The residue was purified by flash chromatographyeluting with MeOH/DCM=5%-10% to get the crude intermediate (7 g) whichwas mixed with PPA (60 g), heated to 180° C. and stirred for 24 h. Thenthe mixture was cooled to 60° C., ice (100 g) was added carefully tobreak the gum. The mixture was treated with 2M NaOH to pH=8 andextracted with EtOAc (3×200 mL). The combined organic layers wereconcentrated under reduced pressure. The residue was triturated with EAto give 6-benzyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine(2.2 g, 30.2%) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=264.0.

9H-Pyrimido[4,5-b]indole (Intermediate S)

A mixture of 5-bromopyrimidin-4-amine (1 g, 5.78 mmol), iodobenzene(1.18 g, 5.78 mmol), xantphos (334 mg, 0.578 mmol), sodium tert-butoxide(1.66 g, 17.34 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.52g, 0.58 mmol) in dioxane was degassed with nitrogen, heated to 110° C.and stirred for 24 hours. The reaction was cooled to r.t, poured intowater and extracted with EtOAc (3×100 mL). The combined organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by flash chromatography(EtOAc/DCM=80%) to give 9H-pyrimido[4,5-b]indole (370 mg, 37.9% yield)as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=170.0.

8H-Thieno[2,3-b]indole (Intermediate T)

Step 1. 3-(2-nitrophenyl)thiophene

A solution of thiophen-3-ylboronic acid (1.9 g, 14.9 mmol),1-bromo-2-nitrobenzene (2 g, 9.90 mmol), Pd(PPh₃)₄(572 mg, 0.495 mmol),K₂CO₃ (2.7 g, 19.8 mmol) in H₂O/DMF (10 mL/30 mL) was heated to 80° C.and stirred under N₂ overnight. To the mixture was added H₂O (50 mL),extracted with EA (100 mL). The organic layer was washed with brine (30mL), dried over Na₂SO₄, filtered, concentrated and purified by column(PE/EA=100/1 to 50/1 to 20/1) to give the product3-(2-nitrophenyl)thiophene (1.6 g, 50% yield) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 7.79 (dd, J=1.2 Hz, J=8.0 Hz, 1H), 7.60-7.56 (m, 1H),7.50-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.33-7.32 (m, 1H), 7.08 (dd, J=1.2Hz, J=5.2 Hz, 1H).

Step 2: 8H-thieno[2,3-b]indole

A mixture of 3-(2-nitrophenyl)thiophene (800 mg, 3.88 mmol), Pd(OAc)₂(17 mg, 0.078 mmol), 1,10-phenanthroline (28 mg, 0.155 mmol) and DMF (15mL) was heated to 140° C. and stirred for 16 h under CO (70 psi). To thecooled mixture was added H₂O (50 mL), extracted with EA (100 mL). theorganic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, concentrated and purified by column (PE/EA=100/1 to 50/1 to20/1) to give product 8H-thieno[2,3-b]indole (500 mg, 74% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (br s, 1H), 7.81-7.79 (m,1H), 7.43-7.41 (m, 1H), 7.35 (d, J=5.2 Hz, 1H), 7.27-7.17 (m, 2H), 6.89(d, J=5.2 Hz, 1H).

5-Bromo-8H-thieno[2,3-b]indole (Intermediate U)

Step 1: 3-(5-bromo-2-nitrophenyl)thiophene

A solution of thiophen-3-ylboronic acid (0.9 g, 7.12 mmol),2,4-dibromo-1-nitrobenzene (2 g, 7.12 mmol), Pd(PPh₃)₄(247 mg, 0.214mmol) and NaOH (854 mg, 21.4 mmol) in dioxane/H₂O (50 mL/10 mL) washeated to 100° C. and stirred under N₂ overnight. To the mixture wasadded H₂O (50 mL), extracted with EA (100 mL). The organic layer waswashed with brine (50 mL), dried over Na₂SO₄, filtered, concentrated andpurified by column and prep-HPLC to give product3-(5-bromo-2-nitrophenyl)thiophene (300 mg, 33% yield) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J=8.4 Hz, 1H), 7.66 (d, J=2.0 Hz,1H), 7.59 (dd, J=2.0 Hz, J=8.8 Hz, 1H), 7.41-7.39 (m, 1H), 7.36-7.35 (m,1H), 7.06 (dd, J=1.2 Hz, J=5.2 Hz, 1H).

Step 2: 5-bromo-8H-thieno[2,3-b]indole

To a solution of 3-(5-bromo-2-nitrophenyl)thiophene (250 mg, 0.880 mmol)in THF (10 mL) was added PhMgBr (1 N in THF) at 0° C. and stirred for 2h at 0° C. under N₂. To the mixture was added aq. NH₄Cl (20 mL),extracted with EA (50 mL). The organic layer was washed with brine (30mL), dried over Na₂SO₄, filtered, concentrated and purified by column(PE/EA=20/1 to 10/1 to 4/1) to give product5-bromo-8H-thieno[2,3-b]indole (100 mg, 45% yield) as a white solid.

4H-Thiazolo[4,5-b]indole (Intermediate V)

Step 1: 5-(2-nitrophenyl)thiazole

A mixture of 5-bromothiazole (200 mg, 1.2 mmol), (2-nitrophenyl)boronicacid (306 mg, 1.8 mmol), Na₂CO₃ (259 mg, 2.4 mmol) and Pd(PPh₃)₄(141 mg,0.1 mmol) in DMA (5 mL) was degassed with nitrogen, heated to 150° C.and stirred for 2 hours under nitrogen atmosphere and microwave. Thereaction was cooled to r.t, filtered and concentrated in vacuo. Theresidue was diluted with water, extracted with EA. The combined organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography to give 5-(2-nitrophenyl)thiazole (130 mg, 52% yield) asa yellow solid. LC/MS (ESI, m/z): [M+1]⁺=207.2

Step 2: 4H-thiazolo[4,5-b]indole

A mixture of 5-(2-nitrophenyl)thiazole (100 mg, 0.5 mmol) and PPh₃ (382mg, 1.5 mmol) in DCB (3 mL) was heated at 200° C. for 2 hrs undermicrowave condition. The reaction mixture was cooled to r.t, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography to give 4H-thiazolo[4,5-b]indole (60 mg, 72%yield) as a yellow oil. LC/MS (ESI, m/z): [M+1]⁺=175.2.

4H-Thiazolo[5,4-b]indole (Intermediate W)

Step 1: 4-(2-nitrophenyl)thiazole

A mixture of 4-bromothiazole (3.0 g, 18.3 mmol), (2-nitrophenyl)boronicacid (4.6 g, 27.4 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0g, 0.91 mmol) and sodium carbonate (3.9 g, 36.6 mmol) in DMA (15 mL) andwater (0.5 mL) was degassed with nitrogen, heated to 150° C. and stirredfor 2 hours under microwave condition. The reaction was cooled to r.tand filtered. The filtrate was diluted with water, extracted with EA.The combined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography (Petroleum ether/EtOAc=4:1) to give4-(2-nitrophenyl)thiazole (2.35 g, 62.3% yield) as a yellow solid. LC/MS(ESI, m/z): [M+1]⁺=207.1.

Step 2: 4H-thiazolo[5,4-b]indole

A mixture of 4-(2-nitrophenyl)thiazole (2.1 g, 10.2 mmol) and PPh₃ (8.0g, 30.6 mmol) in DCB (15 mL) was heated at 200° C. for 2 h undermicrowave condition. The reaction mixture was cooled to r.t, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography (Petroleum ether/Ethyl acetate=2 to 1) to give4H-thiazolo[5,4-b]indole (0.7 g, 39.5% yield) as a yellow solid. LC/MS(ESI, m/z): [M+1]⁺=175.1.

5-Phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (Intermediate X)

Step 1: N-(2-benzoylphenyl)-2-bromoacetamide

A mixture of (2-aminophenyl)(phenyl)methanone (394 mg, 2.0 mmol), NaHCO₃(336 mg, 4.0 mmol) and 2-bromoacetyl bromide (482 mg, 2.4 mmol) in CHCl₃was degassed with nitrogen, the mixture was stirred at r.t for 16 hoursunder nitrogen atmosphere. The residue was diluted with water, extractedwith DCM. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, concentrated in vacuo to giveN-(2-benzoylphenyl)-2-bromoacetamide (600 mg) which was used for nextstep without further purification. LC/MS (ESI, m/z): [M+1]⁺=319.1.

Step 2: 5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one

A solution of N-(2-benzoylphenyl)-2-bromoacetamide (600 mg, 2.0 mmol)was dissolved in NH₃/MeOH at 0° C., then heated to 70° C. and stirredfor 16 hours under nitrogen atmosphere. The reaction was cooled to r.tand stirred at r.t for 16 hours under nitrogen atmosphere. The mixturewas concentrated in vacuo. The residue was purified by columnchromatography to give5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (150 mg, two steps32% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=237.2.

9H-Benzo[d]imidazo[1,2-a]imidazole (Intermediate Y)

Step 1: 1-(2,2-diethoxyethyl)-1H-benzo[d]imidazol-2-amine

To a solution of 1H-benzo[d]imidazol-2-amine (665 mg, 5.0 mmol) in DMF(10 mL) was added KOH (0.56 g, 10.0 mmol). The reaction mixture wasstirred for 40 h at 100° C. The reaction mixture was cooled to roomtemperature, diluted with water and extracted with EtOAc. The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography to give1-(2,2-diethoxyethyl)-1H-benzo[d]imidazol-2-amine (410 mg, 32.8% yield)as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=250.3.

Step 2: 9H-benzo[d]imidazo[1,2-a]imidazole

To a solution of 1-(2,2-diethoxyethyl)-1H-benzo[d]imidazol-2-amine (330mg, 1.33 mmol) in conc. HCl (10 mL) was heated to 100° C. and stirredfor 17 h. The reaction mixture was cooled to room temperature, pouredinto ice-water. The mixture was filtered and the solid was purified bysilica gel column chromatography to give9H-benzo[d]imidazo[1,2-a]imidazole (70 mg, 35.0% yield) as a yellowsolid. LC/MS (ESI, m/z): [M+1]⁺=158.1.

EXAMPLES Example 1. 3-(9H-Carbazol-9-yl)piperidine-2,6-dione (I-1)

Step 1. 3-(9H-Carbazol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of 9H-carbazole (2.0 g, 12.0 mmol) in DMF (20 mL) wasadded t-BuOK (1.61 g, 14.4 mmol) at 0° C. The mixture was stirred at0-10° C. for 1 hour under N₂. Then3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (5.59 g, 18.0 mmol) inDMF (30 mL) was added to the reaction mixture at 0-10° C. during 20minutes. After addition, the mixture was stirred at room temperature for17 hours under N₂. On completion, the reaction was quenched by water andextracted with EA. The combined organic layer was washed with water andbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography to give the titledcompound (0.35 g, 7.4% yield) as a yellow solid. LC-MS (ESI⁺): m/z 399.3(M+H)⁺.

Step 2. 3-(9H-Carbazol-9-yl)piperidine-2,6-dione

To a solution of3-(9H-carbazol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (0.1 g,0.25 mmol) in CH₃CN (4 mL) was added Diammonium cerium(IV) nitrate (0.41g, 0.75 mmol) in water (1 mL) at 0° C. The reaction mixture was stirredat this temperature for 1 hour, then diluted with water. The mixture waspurified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) togive the titled compound (7.5 mg, 10.7%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.49 (dd, J=7.5, 1.3 Hz, 1H), 8.25 (d, J=7.5 Hz, 1H),8.11-8.01 (m, 1H), 7.88 (s, 1H), 7.57-7.40 (m, 3H), 7.34-7.29 (m, 2H),5.51 (m, 1H), 3.08-2.94 (m, 2H), 2.74-2.53 (m, 2H). LC-MS (ESI⁺): m/z279.2 (M+H)⁺.

Example 2. 3-(9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-2)

Step 1.1-(4-Methoxybenzyl)-3-(9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of 9H-pyrido[2,3-b]indole (2 g, 12 mmol) in DMF (30 mL)was added t-BuOK (1.34 g, 12 mmol) at 0° C. The mixture was stirred at0-10° C. for 2 hour under N₂. Then a solution of3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (5.6 g, 18 mmol) in DMF(20 mL) was added to the reaction mixture at 0-10° C. during 30 minutes.The mixture was warmed to room temperature and stirred for 30 minutesunder N₂. The reaction was quenched water (50 mL) and extracted with EA(3×50 mL). The combined organic layer was concentrated in vacuo. Theresidue was purified by column chromatography (PE/EA) to give the crudecompound mix with the 9H-pyrido[2,3-b]indole. Then the mixture waspurified with prep HPLC eluting with ACN/H₂O (0.1% HCOOH) to get thetitle compound (538 mg) as a white solid (yield: 11.2%). LC-MS (ESI⁺):m/z 400.1 (M+H)⁺.

Step 2. 3-(9H-Pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of1-(4-methoxybenzyl)-3-(9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(400 mg, 1 mmol) in toluene (10 ml) was added MsOH (1.8 g, 20 mmol). Themixture was warmed to 100° C. and stirred for 2 h. The reaction mixturewas cooled to room temperature and concentrated in vacuo. The residuewas poured into ice/water (50 mL), extracted with EA (3×50 mL). Thecombined organic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified with prepHPLC eluting with ACN/H₂O (0.1% HCOOH) to get the titled compound (120mg, 43% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 11.15 (s,1H), 8.53-8.62 (m, 1H), 8.43 (dd, J=4.88, 1.50 Hz, 1H), 8.24 (d, J=7.63Hz, 1H), 7.62 (d, J=7.88 Hz, 1H), 7.46-7.56 (m, 1H), 7.24-7.37 (m, 2H),6.05 (br. s., 1H), 2.93-3.21 (m, 2H), 2.63-2.77 (m, 1H), 2.07-2.18 (m,1H). LC-MS (ESI⁺): m/z 280.0 (M+H)⁺.

Example 3. 3-(6-Amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-5)

Step 1. 6-Nitro-9H-pyrido[2,3-b]indole

To a solution of 9H-pyrido[2,3-b]indole (504 mg, 3 mmol) in conc. H₂SO₄(5 ml) was added dropwise a solution of nitric acid (68%-70% solution inwater)(297 mg, 3.3 mol) in con.H₂SO₄(5 ml) at −5° C.-0° C. over 20 mins.After addition, the mixture was added into ice water, then basified byaddition of saturated NaOH solution to PH>8. The mixture was extractedwith EtOAc (3*200 ml), the combined organic layers were evaporated togive the title compound as a yellow solid (500 mg, 78.2% yield) that wasused directly in the next step without further purification. LC-MS(ESI⁺): m/z 214.2 (M+H)⁺.

Step 2. tert-Butyl 6-nitro-9H-pyrido[2,3-b]indole-9-carboxylate

To a solution of 6-nitro-9H-pyrido[2,3-b]indole (500 mg, 2.35 mmol) inDCM (10 ml) was added Boc₂O (767 mg, 3.52 mmol) and DMAP (57.2 mg, 0.468mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was evaporated. The residue was purified by silica gelchromatography (PE:EA=3:1) to give the title compound as a white solid(385 mg, 52.1% yield). 1H NMR (400 MHz, CDCl₃) δ: 8.90 (d, J=2.13 Hz,1H), 8.75 (dd, J=4.82, 1.56 Hz, 1H), 8.35-8.47 (m, 3H), 7.44 (dd,J=7.75, 4.88 Hz, 1H), 1.80 (s, 9H).

Step 3. 6-Nitro-9H-pyrido[2,3-b]indole

To a solution of tert-butyl 6-nitro-9H-pyrido[2,3-b]indole-9-carboxylate(300 mg, 0.96 mmol) in DCM (6 ml) was added TFA (2 ml). The mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated. The residue was resolved in DCM (20 ml), washed withsaturated NaHCO₃ solution (2*20 ml), the organic phase was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to give thecrude titled compound (200 mg, 95.4% yield) as a yellow solid. LC-MS(ESI⁺): m/z 214.2 (M+H)⁺

Step 4.1-(4-Methoxybenzyl)-3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of 6-nitro-9H-pyrido[2,3-b]indole (210 mg, 1 mmol) in THF(10 mL) was added t-BuOK (168 mg, 1.5 mmol) at 0° C. The mixture wasstirred at 0-10° C. for 1 hour under N₂. Then a solution of[1-[(4-methoxyphenyl) methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (457 mg, 1.2 mmol) in THE(10 mL) was added to the reaction mixture at 0-10° C. during 20 minutes.The mixture was stirred at 0-10° C. for 30 minutes under N2. Additionalsolution of [1-[(4-methoxyphenyl) methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (114 mg, 0.3 mmol) in THE(5 mL) was added to the reaction mixture at 0-10° C. dropwise. Themixture was stirred at 0-10° C. for another 30 minutes under N2. Oncompletion, the reaction was quenched water (40 mL) and extracted withEA (3×50 mL). The combined organic layer was concentrated in vacuo. Theresidue was purified by column chromatography to give the titledcompound (400 mg) as a yellow solid. LC-MS (ESI⁺): m/z 445(M+H)⁺.

Step 5. 3-(6-Nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of1-(4-methoxybenzyl)-3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(400 mg, 0.90 mmol) in CH₃CN (10 ml) was added a solution of CAN (2.46g, 0.45 mmol) in water (3 ml) at 0° C. After addition, the mixture waswarmed to room temperature and stirred overnight. The reaction mixturewas poured into water (50 ml), extract with EtOAc (3*50 ml), thecombined organic layers were concentrated in vacuo. The residue wastriturated with DMF/EA and filtrated to give the titled compound (130mg, 44.4% yield) as a grey solid. LC-MS (ESI⁺): m/z 325.0 (M+H)⁺.

Step 6. 3-(6-Amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-5)

To a solution of3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (130 mg,0.401 mmol) in THE (5 ml) and EA (5 ml) was added palladium on activatedcarbon 10% Pd (50 mg) The mixture was stirred at room temperature underhydrogen overnight. The reaction mixture was filtered, the filtrate wasconcentrated under reduce pressure, the residue was triturated withDMF/EA and filtrated to give the title compound (55 mg, 46.4% yield) asa grey solid. LC-MS (ESI⁺): m/z 295.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6)δ: 11.08 (s, 1H), 8.26-8.39 (m, 2H), 7.24-7.36 (m, 2H), 7.14 (dd,J=7.63, 4.88 Hz, 1H), 6.85 (dd, J=8.63, 2.13 Hz, 1H), 5.90 (br. s., 1H),4.87 (br. s., 2H), 2.93-3.08 (m, 2H), 2.68 (d, J=12.26 Hz, 1H),2.01-2.11 (m, 1H).

Example 4.N-(9-(2,6-Dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)acetamide(I-8)

To a solution of3-(6-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (40 mg crude,0.136 mmol) in ACN (5 ml) was added acetic anhydride (5 drops) and DIPEA(10 drops). The mixture was stirred at room temperature for 2 h. Themixture was filtered, the filtrate cake was dissolved in DCM, washedwith 1M HCl (2*10 ml), the organic phase was concentrated and dried togive the titled compound (8 mg, 17.4% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ: 11.14 (s, 1H), 10.02 (s, 1H), 8.45-8.55 (m, 2H),8.35-8.45 (m, 1H), 7.46-7.61 (m, 2H), 7.25 (dd, J=7.69, 4.82 Hz, 1H),6.02 (br. s., 1H), 2.93-3.17 (m, 2H), 2.63-2.76 (m, 1H), 2.06-2.14 (m,4H). LC-MS (ESI⁺): m/z 337.0 (M+H)⁺.

Example 5.1-(9-(2,6-Dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)-3-ethylurea(I-9)

To a solution of3-(6-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (25 mg, 0.085mmol) in ACN (5 ml) was added ethyl isocyanate (3 drops) and DIPEA (6drops). The mixture was stirred at room temperature for 4 h. The mixturewas concentrated in vacuo and the residue was purified by prep HPLC togive the title compound (8 mg, 25.7% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ: 11.13 (s, 1H), 8.43-8.54 (m, 2H), 8.39 (dd,J=4.82, 1.44 Hz, 1H), 8.27 (d, J=1.88 Hz, 1H), 7.37-7.52 (m, 2H), 7.22(dd, J=7.63, 4.88 Hz, 1H), 6.12 (t, J=5.50 Hz, 1H), 5.99 (br. s., 1H),3.10-3.20 (m, 2H), 2.90-3.07 (m, 2H), 2.65-2.75 (m, 1H), 2.06-2.16 (m,1H), 1.03-1.13 (m, 3H). LC-MS (ESI⁺): m/z 366.3 (M+H)⁺.

Example 6. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) Assay

Equal volumes of His-tagged CRBN-DDB1 complex (56 nM) was mixed withEu-cryptate labeled Anti-6HIS-monoclonal antibody (50× dilution from thecommercial stock solution, Vender: Cisbio, Cat. #61HI2KLA) in a finalbuffer containing 20 mM HEPES pH 7.0, 150 mM NaCl, 0.005% Tween-20. Thesolution was then mixed with Cy5-labeled thalidomide (final 8 nM) andvarious concentrations of compounds (a serial 3-fold dilution with thetop concentration 200 uM). The mixture were incubated at roomtemperature for 1 hour. FRET signals were measured on an EnVision platereader (Perkin Elmer) by exciting at 340 nm and recording emission atboth 615 nm as no FRET control and 665 nm as the FRET signals with a 60microsecond delay. FRET efficiency was calculated as the ratio offluorescent signals at 665 nM/615 nM. Quantitative loss of FRETefficiency as a function of compound concentrations was fitted by afour-parameter Logistic Function using GraphPad Prism 7.0 and the IC₅₀values were reported for each compound.

Table 3 shows the results for selected compounds in the time-resolvedfluorescence resonance energy transfer (TR-FRET) assay. The compoundnumbers correspond to the compound numbers in Table 1. Compounds havingan activity designated as “A” provided an IC₅₀ of <10 μM; compoundshaving an activity designated as “B” provided an IC₅₀ of 10-30 μM;compounds having an activity designated as “C” provided an IC₅₀ of30-100 μM; and compounds having an activity designated as “D” providedan IC₅₀ of >100 μM. For reference, the known CRBN binders provided thefollowing IC₅₀ values in the TR-FRET assay: thalidomide (IC₅₀=2.9 μM),lenalidomide (IC₅₀=1.17 μM) and pomalidomide (IC₅₀=1.28 μM).

TABLE 3 TR-FRET Assay Results CRBN HTRF CMPD # IC₅₀ (μM) I-1 B I-2 A I-3C I-5 A I-8 A I-9 A I-26 A I-27 A I-28 A I-29 B I-30 A I-31 A I-32 BI-33 A I-34 A I-35 A I-36 A I-37 B I-38 A I-39 A I-40 B I-41 C I-42 DI-43 C I-44 A I-45 B I-46 A I-47 A I-48 A I-49 A I-50 A I-51 A I-52 AI-53 B I-54 B I-55 C I-56 B I-57 A I-58 B I-59 A I-60 A I-61 A I-62 AI-63 A I-64 A I-65 C I-66 B I-67 B I-68 C I-69 D I-70 B I-71 A I-72 AI-73 B I-74 B I-75 A I-76 A I-77 A I-78 A I-79 A I-80 B I-81 B I-82 BI-83 A I-84 A I-85 B I-86 A I-87 A I-88 A I-89 A I-90 B I-91 C I-92 AI-93 A I-94 C I-99 C I-100 A I-101 A I-102 B I-103 A I-105 B I-106 B

Example 7. General Method A.3-(6-Bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (1-26),tert-Butyl(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate(I-33), and tert-butyl(2-(3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)propoxy)ethyl)carbamate(I-34)

Step 1:3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a stirred solution of Intermediate A (200 mg, 0.810 mmol) and18-crown-6 (43 mg, 0.162 mmol) in dry THF (10 mL) was added dropwiseNaHMDS (0.6 mL, 2 M in THF) at −30° C. under N₂. The mixture was stirredfor 1 h at −30° C. under N₂. Then to the mixture was added a solution of1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate(463 mg, 1.21 mmol) in THF (5 mL) dropwise at−30° C. under N₂. Themixture was stirred at −30° C. for 2 h. The mixture was added to aq.NH₄Cl (20 mL), extracted with EA (50 mL). The organic layer was washedwith brine (30 mL), dried over Na₂SO₄, filtered, concentrated andpurified by column (PE/EA/DCM=10/1/1 to 3/1/1) to give product3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(220 mg, 57% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (dd,J=1.6 Hz, J=4.8 Hz, 1H), 8.29 (dd, J=1.2 Hz, J=7.6 Hz, 1H), 8.20 (J=1.6Hz, 1H), 7.45 (dd, J=2.0 Hz, J=8.6 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H),7.24-7.21 (m, 1H), 6.84 (d, J=8.8 Hz, 3H), 5.90-5.87 (m, 1H), 5.01 (dd,J=13.6 Hz, J=20.4 Hz, 2H), 3.81 (s, 3H), 3.09-2.84 (m, 4H); LC/MS (ESI,m/z): [M+1]⁺=479.1.

Step 2: 3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-26)

A mixture of3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(1.3 g, 2.72 mmol), MsOH (10 mL) and toluene (20 mL) was heated to 110°C. and stirred for 3 h under N₂. The mixture was concentrated to removetoluene. Then to the mixture was added EA (50 mL), washed with brine (50mL) to remove MsOH. The organic layer was dried over Na₂SO₄,concentrated with silica gel and purified by column (PE/EA=1/1) to giveproduct I-26 (500 mg, 51% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.13 (br s, 1H), 8.64 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 8.52 (d,J=2.0 Hz, 1H), 8.47 (dd, J=1.6 Hz, J=4.8 Hz, 1H), 7.68-7.62 (m, 2H),7.31 (dd, J=4.8 Hz, J=7.6 Hz, 1H), 6.06 (s, 1H), 3.16-2.96 (m, 2H),2.73-2.67 (m, 1H), 2.16-2.13 (m, 1H). LC/MS (ESI, m/z):[M+1]⁺=358.0/360.0.

Step 3: tert-butyl(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate(I-33)

A mixture of I-26 (100 mg, 0.279 mmol), tert-butyl(2-(prop-2-yn-1-yloxy)ethyl)carbamate (166 mg, 0.840 mmol), Pd(PPh₃)₂Cl₂(30 mg, 0.042 mmol), CuI (4 mg, 0.022 mmol), TEA (283 mg, 2.80 mmol),and DMF (5 mL) was heated to 80° C. under microwave for 1.5 h under N₂.The mixture was poured into 1N HCl (20 mL), extracted with EA (50 mL).The organic layer was washed with brine (20 mL), dried over Na₂SO₄,filtered, concentrated and purified by column (PE/EA=10/1 to 5/1 to 2/1)to give product I-33 (30 mg, 23% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.17 (s, 1H), 8.62 (dd, J=1.2 Hz, J=7.6 Hz, 1H), 8.46(dd, J=1.6 Hz, J=4.8 Hz, 1H), 8.43 (s, 1H), 7.66-7.58 (m, 2H), 7.33-7.30(m, 1H), 8.87 (s, 1H), 6.07 (br s, 1H), 4.42 (s, 2H), 3.54 (t, J=6.0 Hz,2H), 3.17-3.01 (m, 4H), 2.69-2.66 (m, 1H), 2.16-2.13 (m, 1H), 1.38 (s,9H). LC/MS (ESI, m/z): [M+1]⁺=477.2.

Step 4: tert-butyl(2-(3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)propoxy)ethyl)carbamate(I-34)

A mixture of tert-butyl I-33 (10 mg, 0.021 mmol), Pd/C (2 mg) and EA (2mL) was stirred for 12 h under H₂ at rt. The mixture was filtered, addedH₂O (10 mL), extracted with EA (20 mL). The organic layer wasconcentrated and purified by Prep-HPLC to give product I-34 (3 mg, 30%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 8.53(d, J=7.6 Hz, 1H), 8.40 (d, J=4.4 Hz, 1H), 8.05 (s, 1H), 7.52 (d, J=8.0Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.26-7.23 (m, 1H), 6.81 (t, J=5.2 Hz,1H), 6.01 (br s, 1H), 3.43-3.39 (m, 3H), 3.19-2.97 (m, 4H), 2.79 (t,J=7.2 Hz, 2H), 2.72-2.68 (m, 1H), 2.12-2.10 (m, 1H), 2.03-1.96 (m, 1H),1.91-1.85 (m, 2H), 1.37 (m, 9H); LC/MS (ESI, m/z): [M−55]⁺=425.2.

Characterization data for further compounds prepared by Method A arepresented in Table 4 below. Compounds in Table 4 were prepared bymethods substantially similar to the steps described to prepare I-26,I-33, and I-34.

TABLE 4 Compounds prepared according to Method A. LC/MS I-#Intermediates (ESI, m/z) ¹H NMR (400 MHz) I-33 I-26 + B [M + 1]⁺ =(CDCl₃) δ 8.45 (dd, J = 1.2 Hz, J = 5.0 Hz, 1 H), 8.33 (dd, 505.2 J =1.6 Hz, J = 7.6 Hz, 1 H), 8.20 (d, J = 1.2 Hz, 1 H), 8.10 (s, 1 H), 7.58(dd, J = 1.6 Hz, J = 8.4 Hz, 1 H), 7.25-7.20 (m, 2 H), 5.91-5.88 (m, 1H), 4.41 (s, 2 H), 3.64 (t, J = 6.8 Hz, 2 H), 3.34 (t, J = 7.2 Hz, 2 H),310-2.91 (m, 3 H), 2.89 (s, 3 H), 2.36-2.30 (m, 1 H), 1.91-1.84 (m, 2H), 1.46 (s, 9 H) I-34 I-33 [M − 55]⁺ = (CDCl₃) δ 8.41 (dd, J = 1.6 Hz,J = 4.8 Hz, 1 H), 8.32 (d, 453.2 J = 7.6 Hz, 1 H), 8.15 (s, 1 H), 7.91(d, J = 0.8 Hz, 1 H), 7.33 (dd, J = 1.6 Hz, J = 8.4 Hz, 1 H), 7.21 (d, J= 5.2 Hz, J = 7.6 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 5.94 (br s, 1 H),3.47- 3.42 (m, 4 H), 3.31 (t, J = 6.8 Hz, 2 H), 3.07-2.95 (m, 3 H),2.88-2.84 (m, 5 H), 2.33-2.29 (m, 1 H), 2.01-1.93 (m, 2 H), 1.85-1.78(m, 2 H), 1.46 (s, 9 H); I-47 I-26 + ((2-(2- [M + 1]⁺ = (CDCl₃) δ 8.44(dd, J = 1.2 Hz, J = 4.8 Hz, 1 H), 8.30 (dd, (prop-2-yn-1- 512.2 J = 1.2Hz, J = 7.6 Hz, 1 H), 8.20 (d, J = 0.8 Hz, 1 H), 8.17 yloxy)eth-oxy)eth-(br s, 1 H), 7.57 (dd, J = 1.4 Hz, J = 8.4 Hz, 1 H), 7.37-7.31oxy)methyl)benzene (m, 4 H), 7.29-7.18 (m, 3 H), 5.87-5.84 (m, 1 H),4.58 (s, 2 H), 4.48 (s, 2 H), 3.83-3.80 (m, 2 H), 3.77-3.71 (m, 4 H),3.69-3.64 (m, 2 H), 3.09-2.92 (m, 3 H), 2.32-2.28 (m, 1 H). I-46 I-47[M + 1]⁺ = (CDCl₃) δ 8.41 (dd, J = 1.2 Hz, J = 4.8 Hz, 1 H), 8.31 (dd,426.1 J = 1.4 Hz, J= 7.6 Hz, 1 H), 8.28 (s, 1 H), 7.92 (d, J = 0.4 Hz, 1H), 7.33 (dd, J = 1.2 Hz, J = 8.4 Hz, 1 H), 7.21-7.16 (m, 2 H), 5.90(dd, J = 4.8 Hz, J = 8.0 Hz, 1 H), 3.76-3.74 (m, 2 H), 3.71-3.69 (m, 2H), 3.65-3.60 (m, 4 H), 3.52 (t, J = 6.4 Hz, 2 H), 3.08-2.85 (m, 5 H),2.59 (br s, 1 H), 2.32-2.26 (m, 1 H), 2.04-1.97 (m, 2 H). I-63 I-26 + C[M − (CDCl₃) δ 8.45 (dd, J = 1.2 Hz, J = 4.8 Hz, 1vH), 8.34 (dd, Boc +1]⁺ = J = 0.8 Hz, J = 7.6 Hz, 1 H), 8.21 (d, J = 0.8 Hz, 1 H), 8.15421.3 (s, 1 H), 7.59 (dd, J = 1.2 Hz, J = 8.4 Hz, 1 H), 7.26-7.18 (m, 2H), 5.95-5.89 (m, 1 H), 5.01 (br s, 1 H), 4.48 (s, 2 H), 3.81-3.79 (m, 2H), 3.71-3.69 (m, 2 H), 3.58 (t, J = 5.2 Hz, 2 H), 3.35 (dd, J = 4.8 Hz,J = 9.2 Hz, 2 H), 3.09-2.88 (m, 3 H), 2.35-2.31 (m, 1 H), 1.44 (s, 9 H)I-62 I-63 [M − (CDCl₃) δ 8.41 (dd, J = 1.2 Hz, J = 4.8 Hz, 1 H), 8.31(dd, Boc + 1]⁺ = J = 1.6 Hz, J = 7.6 Hz, 1 H), 8.22 (br s, 1 H), 7.92(d, J = 0.8 425.2 Hz, 1 H), 7.33 (dd, J = 1.6 Hz, J = 8.4 Hz, 1 H),7.21-7.16 (m, 2 H), 5.90 (dd, J = 4.8 Hz, J = 12 Hz, 1 H), 5.04 (br s, 1H), 3.64-3.50 (m, 8 H), 3.35-3.32 (m, 2 H), 3.12-2.85 (m, 5 H),2.32-2.28 (m, 1 H), 2.04-1.97 (m, 2 H), 1.43 (s, 9 H); I-32 E [M + 1]⁺ =(DMSO-d₆) δ 11.22 (s, 1 H), 8.85 (d, J = 1.3 Hz, 1 H), 8.72- 305.3 8.69(m, 1 H), 8.55-8.53 (m, 1 H), 7.95-7.83 (m, 2 H), 7.40 (dd, J = 7.7, 4.9Hz, 1 H), 6.13 (s, 1 H), 3.18-2.98 (m, 2 H), 2.80-2.63 (m, 1 H),2.24-2.09 (m, 1 H) I-31 F [M + 1]⁺ = (DMSO-d₆) δ. 11.19 (s, 1 H), 8.57(d, J = 8.0 Hz, 1 H), 8.31 358.0, (d, J = 5.2 Hz, 1 H), 7.72 (s, 1 H),7.63 (t, J = 7.6 Hz, 1 H), 360.0 7.56 (d, J = 5.2 Hz, 1 H), 7.41 (t, J =7.4 Hz, 1 H), 6.10 (s, 1 H), 3.13-2.99 (m, 2 H), 2.74-2.67 (m, 1 H),2.17-2.15 (m, 1 H) I-49 I-31 + ((2-(2- [M + 1]⁺ = (CDCl₃) δ 8.54 (d, J =7.8 Hz, 1 H), 8.35 (d, J = 5.1 Hz, 1 (prop-2-yn-1- 512.3 H), 8.26 (s, 1H), 7.56-7.45 (m, 1 H), 7.36-7.29 (m, 6 H), yloxy)ethoxy)eth- 7.27-7.25(m, 1 H), 7.22 (d, J = 5.1 Hz, 1 H), 5.90-5.86 oxy)methyl)benzene (m, 1H), 4.66 (s, 2 H), 4.57 (s, 2 H), 3.91-3.88 (m, 2 H), 3.79-3.76 (m, 2H), 3.76-3.71 (m, 2 H), 3.69-3.63 (m, 2 H), 3.12-2.86 (m, 3 H),2.32-2.25 (m, 1 H) I-48 I-49 [M + 1]⁺ = (CDCl₃) δ 8.43-8.26 (m, 2 H),8.18 (d, J = 7.8 Hz, 1 H), 426.3 7.50-7.45 (m, 1 H), 7.36-7.24 (m, 2 H),7.03 (d, J = 5.0 Hz, 1 H), 5.95-5.92 (m, 1 H), 3.76-3.59 (m, 10 H),3.36- 3.23 (m, 2 H), 3.14-2.84 (m, 3 H), 2.33-2.22 (m, 1 H), 2.21-2.08(m, 2 H) I-57 I-31 + C [M + 1]⁺ = (CDCl₃) δ 8.32 (d, J = 5.1 Hz, 1 H),8.20 (d, J = 7.9 Hz, 1 525.4 H), 8.12 (s, 1 H), 7.52-7.47 (m, 1 H),7.37-7.26 (m, 2 H), 7.07-7.05 (m, 1 H), 5.96 (s, 1 H), 5.00 (s, 1 H),3.66-3.56 (m, 8 H), 3.41-3.24 (m, 4 H), 3.07-2.99 (m, 3 H), 2.34- 2.29(m, 1 H), 2.18-2.11 (m, 2 H), 1.43 (s, 9 H) I-30 G [M + 1]⁺ = (DMSO-d₆)δ 11.19 (s, 1 H), 8.91 (dd, J = 1.2, 7.6 Hz, 1 H), 358.1, 8.53 (d, J =4.0 Hz, 1 H), 7.72 (s, 1 H), 7.56-7.51 (m, 1 H), 360.1 7.49-7.45 (m, 1H), 7.40-7.37 (m, 1 H), 6.19-6.00 (m, 1 H), 3.12-2.99 (m, 2 H),2.74-2.67 (m, 1 H), 2.17-2.14 (m, 1 H) I-52 I-30 + ((2-(2- [M + 1]⁺ =(DMSO-d₆) δ 11.17 (s, 1 H), 8.82 (dd, J = 7.8, 1.6 Hz, 1 H),(prop-2-yn-1- 512.3 8.48 (dd, J = 4.8, 1.6 Hz, 1 H), 7.74-7.69 (m, 1 H),7.53 (t, yloxy)ethoxy)eth- J = 8.0 Hz, 1 H), 7.44-7.19 (m, 7 H), 6.09(s, 1 H), 4.66 (s, oxy)methyl)benzene 2 H), 4.48 (s, 2 H), 3.84-3.73 (m,2 H), 3.71-3.52 (m, 6 H), 3.17-2.93 (m, 2 H), 2.81-2.64 (m, 1 H),2.25-2.04 (m, 1 H) I-51 I-52 [M + 1]⁺ = (DMSO-d₆) δ 11.15 (s, 1 H), 8.55(dd, J = 7.6, 1.6 Hz, 1 H), 426.3 8.42 (d, J = 3.7 Hz, 1 H), 7.48-7.42(m, 2 H), 7.31-7.27 (m, 1 H), 7.19-7.04 (m, 1 H), 6.03 (s, 1 H), 4.59(s, 1 H), 3.66-3.42 (m, 10 H), 3.27-3.17 (m, 2 H), 3.05-2.97 (m, 2 H),2.76-2.64 (m, 1 H), 2.16-2.05 (m, 1 H), 1.99-1.92 (m, 2 H) I-61 I-30 + C[M + 1]⁺ = (DMSO-d₆) δ 11.18 (s, 1 H), 8.81 (dd, J = 7.8, 1.6 Hz, 1 H),360.28 8.50 (dd, J = 4.8, 1.7 Hz, 1 H), 7.73-7.68 (m, 1 H), 7.54 (t, J =7.9 Hz, 1 H), 7.45-7.28 (m, 2 H), 6.80-6.76 (m, 1 H), 6.08 (s, 1 H),4.65 (s, 2 H), 3.81-3.70 (m, 2 H), 3.62 (dd, J = 5.7, 3.6 Hz, 2 H), 3.43(t, J = 6.1 Hz, 2 H), 3.17-2.96 (m, 3 H), 2.76-2.64 (m, 1 H), 2.50-2.45(m, 1 H), 2.17-2.13 (m, 1 H), 1.35 (s, 9 H) I-60 I-61 [M + 1]⁺ =(DMSO-d₆) δ 11.15 (s, 1 H), 8.54 (dd, J = 7.9, 1.5 Hz, 1 H), 525.1 8.42(dd, J = 4.9, 1.5 Hz, 1 H), 7.52-7.40 (m, 2 H), 7.28 (dd, J = 7.8, 4.9Hz, 1 H), 7.11 (d, J = 7.4 Hz, 1 H), 6.77- 6.74 (m, 1 H), 6.10-6.00 (m,1 H), 3.61-3.50 (m, 6 H), 3.43 (t, J = 6.1 Hz, 2 H), 3.23-3.20 (m, 2 H),3.12-2.96 (m, 4 H), 2.72-2.65 (m, 1 H), 2.12-2.06 (m, 1 H), 1.99-1.89(m, 2 H), 1.34 (s, 9 H) I-75 H [M + 1]⁺ = DMSO-d₆) δ 11.21 (s, 1 H),8.63 (d, J = 8.0 Hz, 1 H), 8.26 (d, J = 314.1 8.0, 1 H), 7.64-7.62 (m, 1H), 7.58-7.49 (m, 1 H), 7.40-7.29 (m, 2 H), 6.06-6.00 (m, 1 H),3.12-2.96 (m, 2 H), 2.74-2.66 (m, 1 H), 2.22-2.11 (m, 1 H) I-74 I-75 + C[M + 1]⁺ = (DMSO-d₆) δ 11.17 (s, 1 H), 8.58 (d, J = 7.6 Hz, 1 H), 8.25520.8 (d, J = 8.0 Hz, 1 H), 7.68-7.38 (m, 3 H), 7.32 (t, J = 7.6 Hz, 1H), 6.79 (s, 1 H), 6.05 (s, 1 H), 4.47 (s, 2 H), 3.67- 3.65 (m, 2 H),3.58-3.56 (m, 2 H), 3.40-3.34 (m, 2 H), 3.10-3.05 (m, 4 H), 2.78-2.64(m, 1 H), 2.20-2.09 (m, 1 H), 1.37 (s, 9 H) I-73 I-74 [M + 1]⁺ =(DMSO-d₆) δ 11.14 (s, 1 H), 8.43 (d, J = 7.6 Hz, 1 H), 8.16 525.2 (d, J= 8.0 Hz, 1 H), 7.58-7.56 (m, 1 H), 7.48-7.44 (m, 1 H), 7.30-7.17 (m, 1H), 7.14 (d, J = 8.0 Hz, 1 H), 6.76- 6.73 (m, 1 H), 5.99 (s, 1 H),3.54-3.41 (m, 6 H), 3.40- 3.36 (m, 2 H), 3.08-3.01 (m, 4 H), 2.88 (t, J= 7.6 Hz, 2 H), 2.72-2.65 (m, 1 H), 2.19-2.09 (m, 1 H), 2.01-1.90 (m, 2H), 1.36 (s, 9 H) I-84 I [M + 1]⁺ = (CDCl₃) δ 8.38 (t, J = 7.9 Hz, 1 H).8.12 (br. s., 1 H), 8.05 298.1 (d, J = 7.8 Hz, 1 H), 7.51-7.43 (m, 1 H),7.37-7.30 (m, 1 H), 7.26-7.24 (m, 1H), 6.84-6.82 (m, 1 H), 5.81-5.76 (m,1 H), 3.15-2.88 (m, 3 H), 2.34-2.28 (m, 1 H) I-78 J [M + 1]⁺ = DMSO-d₆)δ 11.10 (s, 1 H), 8.07 (d, J = 8.3 Hz, 1 H), 7.86 295.2 (d, J = 7.5 Hz,1 H), 7.40-7.38 (m, 1 H), 7.25-7.11 (m, 2 H), 6.36 (d, J = 8.3 Hz, 1 H),6.14 (s, 2 H), 5.82-5.78 (m, 1 H), 3.15-2.92 (m, 2 H), 2.72-2.67 (m, 1H), 2.00-2.11 (m, 1 H) I-82 K [M + 1]+ = (DMSO-d₆) δ 11.18 (s, 1 H),8.43 (d, J = 8.3 Hz, 1 H), 8.08 309.3 (dd, J = 8.0, 1.2 Hz, 1 H), 7.59(d, J = 8.2 Hz, 1 H), 7.44- 7.35 (m, 1 H), 7.27-7.21 (m, 1 H), 6.68 (d,J = 8.3 Hz, 1 H), 5.97-5.83 (m, 1 H), 3.90 (s, 3 H), 3.14-2.92 (m, 2 H),2.79-2.65 (m, 1 H), 2.23-2.11 (m, 1 H) I-83 I-82 [M + 1]⁺ = (DMSO-d₆) δ11.14 (s, 1 H), 10.81 (s, 1 H), 8.34 (d, J = 8.3 295.3 Hz, 1 H), 8.01(d, J = 7.7 Hz, 1 H), 7.51 (d, J = 8.3 Hz, 1 H), 7.39-7.29 (m, 1 H),7.21 (t, J = 7.4 Hz, 1 H), 6.52 (d, J = 8.3 Hz, 1 H), 5.85 (dd, J =12.8, 5.2 Hz, 1 H), 3.16 (s, 1 H), 3.04-2.91 (m, 1 H), 2.77-2.64 (m, 1H), 2.14-2.04 (m, 1 H) I-85 L [M + 1]⁺ = (DMSO-d₆) δ 11.24 (s, 1 H),8.86 (d, J = 8.0 Hz, 1 H), 8.38 (d, 348.2 J = 8.0, 1 H), 7.78 (d, J =8.0 Hz, 1 H), 7.73-7.71 (m, 1 H), 7.65- 7.61 (m, 1 H), 7.39 (t, J = 8.0Hz, 1 H), 6.25-5.97 (m, 1 H), 3.21- 2.93 (m, 2 H), 2.83-2.69 (m, 1 H),2.28-2.15 (m, 1 H) I-58 M + C [M + 1]⁺ = (DMSO-d₆) δ 11.13 (s, 1 H),8.49 (dd, J = 7.63, 1.50 Hz, 1 525.3 H), 8.38 (dd, J = 4.75, 1.38 Hz, 1H), 8.11 (d, J = 7.88 Hz, 1 H), 7.47 (br. s., 1 H), 7.24 (dd, J = 7.63,4.88 Hz, 1 H), 7.18-7.12 (m, 1 H), 6.77-6.74 (m, 1 H), 6.01 (br. s., 1H), 3.55-3.47 (m, 4 H), 3.45-3.37 (m, 4 H), 3.11-3.01 (m, 4 H),2.82-2.78 (m, 2 H), 2.73-2.68 (m, 1 H), 2.15-2.05 (m, 1 H), 1.96-1.83(m, 2 H), 1.36 (s, 9 H) I-53 M + ((2-(2- [M + 1]⁺ = (CDCl₃) δ 8.77 (br.s., 1 H), 8.32 (dd, J = 4.9, 1.4 Hz, 1 H), (prop-2-yn-1- 426.2 8.21 (dd,J = 7.6, 1.4 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), yloxy)ethoxy)eth-7.12-7.02 (m, 3 H), 5.90-5.85 (m, 1 H), 3.48-3.73 (m, 8oxy)methyl)benzene H), 3.33-3.44 (m, 2 H), 2.73-3.03 (m, 5 H), 2.15-2.26(m, 1 H), 1.81-1.99 (m, 2 H) I-65 N [M + 1]⁺ = DMSO-d₆) δ 11.14 (s, 1H), 8.23 (d, J = 7.8 Hz, 1 H), 7.92 310.0 (d, J = 5.4 Hz, 1 H),7.86-7.77 (m, 2 H), 7.64-7.56 (m, 1 H), 7.33-7.29 (m, 1 H), 5.94-5.89(m, 1 H), 3.93 (s, 3 H), 3.10-2.97 (m, 1 H), 2.75-2.59 (m, 2 H),2.25-2.13 (m, 1 H) I-42 O [M + 1]⁺ = (DMSO-d₆) δ 12.98 (s, 1 H), 11.53(s, 1 H), 9.47 (s, 1 H), 280.1 8.92 (d, J = 6.8 Hz, 1 H), 8.75 (dd, J =6.8, 1.2 Hz, 1 H), 8.55 (d, J = 7.9 Hz, 1 H), 7.95-7.78 (m, 2 H),7.52-7.48 (m, 1 H), 6.24-6.03 (m, 1 H), 3.06-2.94 (m, 1 H), 2.92- 2.82(m, 2 H), 2.61-2.52 (m, 1 H) I-43 P [M + 1]⁺ = (DMSO-d₆) δ 11.53 (s, 1H), 9.92 (s, 1 H), 8.73 (d, J = 7.1 280.1 Hz, 1 H), 8.36 (d, J = 7.8 Hz,1 H), 8.11 (d, J = 7.1 Hz, 1 H), 7.85-7.73 (m, 2 H), 7.55 (t, J = 7.5Hz, 1 H), 6.00-5.95 (m, 1 H), 2.98-2.79 (m, 3 H), 2.03-1.95 (m, 1 H)I-70 Q [M + 1]⁺ = (DMSO-d₆) δ 11.04 (s, 1 H), 8.08 (dd, J = 4.8, 1.6 Hz,1 H), 284.4 7.78 (dd, J = 7.6, 1.6 Hz, 1 H), 7.02 (dd, J = 7.6, 4.8 Hz,1 H), 5.32 (t, J = 4.9 Hz, 1 H), 2.93 (d, J = 12.1 Hz, 2 H), 2.68- 2.61(m, 5 H), 2.10-1.94 (m, 1 H), 1.85 (d, J = 25.2 Hz, 4 H) I-55 R [M + 1]⁺= (DMSO-d₆) δ 11.06 (s, 1 H), 8.09 (d, J = 3.6 Hz, 1 H), 7.79- 375.27.73 (m, 1 H), 7.42-7.38 (m, 2 H), 7.38-7.33 (m, 2 H), 7.30-7.25 (m, 1H), 7.01 (dd, J = 7.8, 4.8 Hz, 1 H), 5.52 (br. s., 1 H), 3.76 (s, 2 H),3.65-3.55 (m, 2 H), 2.97-2.74 (m, 6 H), 2.66-2.60 (m, 1 H), 2.14-2.06(m, 1 H) I-67^(a) S [M + 1]⁺ = (DMSO-d₆) δ 11.24 (br. s., 1 H), 9.51 (s,1 H), 8.97 (s, 1 281.2 H), 8.33 (d, J = 7.7 Hz, 1 H), 7.74-7.59 (m, 2H), 7.42 (t, J = 7.5 Hz, 1 H), 6.08-6.05 (m, 1 H), 3.11-2.98 (m, 2 H),2.80-2.66 (m, 1 H), 2.24-2.12 (m, 1 H) I-72 T [M + 1]⁺ = (DMSO-d₆) δ11.22 (s, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.58 285.0 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 5.2 Hz, 1 H), 7.27-7.23 (m, 1 H), 7.18-7.13 (m, 2 H),5.90 (dd, J = 4.8 Hz, J = 12.8 Hz, 1 H), 3.03-2.95 (m, 1 H), 2.78-2.65(m, 2 H), 2.27-2.21 (m, 1 H) I-88 U [M + 1]⁺ = DMSO-d₆) δ 11.23 (s, 1H), 8.08 (s, J = 2.0 Hz, 1 H), 7.56 363.0, (d, J = 9.2 Hz, 1 H), 7.50(d, J = 5.2 Hz, 1 H), 7.39 (dd, J = 365.0 2.0 Hz, J = 8.4 Hz, 1 H), 7.18(d, J = 5.2 Hz, 1 H), 5.91 (dd, J = 4.8 Hz, J = 13.2 Hz, 1 H), 3.01-2.92(m, 1 H), 2.77-2.64 (m, 2 H), 2.29-2.22 (m, 1 H) I-66 V [M + 1]⁺ = CDl₃)δ 8.73 (s, 1 H), 8.11 (s, 1 H), 7.79 (d, J = 7.9 Hz, 1 286.0 H),7.41-7.32 (m, 2 H), 7.30-7.26 (m, 1 H), 5.55-5.50 (m, 1 H), 3.26-3.08(m, 1 H), 3.06-2.83 (m, 2 H), 2.44- 2.37 (m, 1 H) I-87 W [M + 1]⁺ =DMSO-d₆) δ 11.24 (s, 1 H), 8.81 (s, 1 H), 7.92 (d, J = 7.5 285.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1 H), 7.40-7.16 (m, 2 H), 6.01-5.96 (m, 1 H),3.06-2.89 (m, 1 H), 2.82-2.58 (m, 2 H), 2.33-2.16 (m, 1 H) I-41^(a) X[M + 1]⁺ = DMSO-d₆) δ 10.98-10.94 (m, 1 H), 7.70-7.63 (m, 1 H), 348.07.61-7.55 (m, 1 H), 7.56-7.38 (m, 5 H), 7.36-7.28 (m, 1 H), 7.26-7.23(m, 1 H), 5.10-4.82 (m, 1 H), 4.56-4.47 (m, 1 H), 3.80-3.70 (m, 1 H),2.90-2.54 (m, 2 H), 2.46- 2.32 (m, 1 H), 2.10-1.73 (m, 1 H) I-94^(b) Y[M + 1]⁺ = DMSO-d₆) δ 11.46 (s, 1 H), 8.30 (d, J = 2.4 Hz, 1 H), 8.14-269.0 8.08 (m, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 2.4 Hz, 1H), 7.59-7.48 (m, 2 H), 5.64 (dd, J = 13.2, 5.2 Hz, 1 H), 2.96-2.87 (m,1 H), 2.81-2.67 (m, 2 H), 2.41-2.39 (m, 1 H) I-99^(b) Y [M + 1]⁺ =DMSO-d₆) δ 11.17 (s, 1 H), 8.20 (s, 1 H), 7.81 (d, J = 7.4 269.0 Hz, 1H), 7.73 (d, J = 1.5 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 7.36-7.27 (m,1 H), 7.28-7.18 (m, 1 H), 7.01 (d, J = 1.5 Hz, 1 H), 5.70-5.66 (m, 1 H),3.10-3.07 (m, 1 H), 2.94- 2.92 (m, 1 H), 2.81-2.75 (m, 1 H), 2.41-2.34(m, 1 H) ^(a)5 equiv. of CAN in CH₃CN/H₂O at 0° C. was used for removalof the PMB group. ^(b)Mixtures of I-94 and I-99 were obtained duringremoval of the PMB group and characterized by NOE after separation.

Example 8. Syntheses of3-(6-(methylamino)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(1-27)

To a mixture of3-(6-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (100 mg, 0.34mmol, I-5) and paraformaldehyde (51 mg, 1.7 mmol) in THF (5 mL) wasadded AcOH (2 drops). The mixture was stirred at room temperature for 1h. Then NaCNBH₃ (42.7 mg, 0.68 mmol) was added in one portion. Thereaction mixture was stirred at room temperature overnight. The reactionmixture was poured into water, extract with EtOAc (3×20 mL). Thecombined organic layers were concentrated under reduced pressure. Theresidue was purified via reverse phase column chromatography(CH₃CN/H₂O=5%-80%) to give I-27 (4.2 mg, 4.0%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.45-8.43 (m, 1H), 8.33 (dd, J=4.9,1.5 Hz, 1H), 7.35-7.32 (m, 1H), 7.29-7.26 (m, 1H), 7.17-7.13 (m, 1H),6.86 (dd, J=8.7, 2.2 Hz, 1H), 5.91 (br. s., 1H), 5.43 (br. s., 1H),3.07-2.96 (m, 2H), 2.78 (s, 3H), 2.71-2.64 (m, 1H), 2.11-2.03 (m, 1H);LC/MS (ESI, m/z): [M+1]⁺=309.34.

Example 9. Synthesis of3-(6-(Dimethylamino)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-28)

To a mixture of I-5 (50 mg, 0.17 mmol) and paraformaldehyde (25.5 mg,0.85 mmol) in THF (5 mL) was added AcOH (2 drops). The mixture wasstirred at room temperature for 1 h. Then NaCNBH₃ (21.3 mg, 0.34 mmol)was added in one portion. The reaction mixture was warmed to 40° C. andstirred overnight. The reaction mixture was poured into water andextract with EtOAc (3×20 mL). The combined organic layers wereconcentrated under reduced pressure. The residue was purified viareverse phase column chromatography (CH₃CN/H₂O=5%-80%) to give I-28 (5.6mg, 10.2%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (dd, J=4.9,1.5 Hz, 1H), 8.22 (dd, J=7.7, 1.5 Hz, 1H), 8.17 (br. s., 1H), 7.40-7.38(m, 1H), 7.10-7.01 (m, 3H), 5.83-5.78 (m, 1H), 3.00-2.78 (m, 9H),2.26-2.13 (m, 1H); LC/MS (ESI, m/z): [M+1]⁺=323.0.

Example 10. Synthesis of ethyl(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)carbamate (I-29)

To a stirred solution of I-5 (51 mg, 0.175 mmol) in MeCN (4 mL) wasadded ethyl carbonochloridate (56 mg, 0.52 mmol) and DIPEA (111 mg,0.865 mmol). The reaction mixture was stirred at r.t for 2 hours. Thereaction mixture was concentrated under reduced pressure and purifiedvia reverse phase column chromatography (CH₃CN/H₂O=5%-80%) to give I-29(7.2 mg, 19.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s,1H), 9.62 (br. s., 1H), 8.49 (dd, J=7.7, 1.6 Hz, 1H), 8.41 (dd, J=4.9,1.5 Hz, 1H), 8.32 (br. s., 1H), 7.58-7.42 (m, 2H), 7.33-7.10 (m, 1H),6.01 (br. s., 1H), 4.16 (q, J=7.1 Hz, 2H), 3.07-2.94 (m, 2H), 2.74-2.64(m, 1H), 2.16-2.02 (m, 1H), 1.27 (t, J=7.1 Hz, 3H); LC/MS (ESI, m/z):[M+1]⁺=367.32.

Example 11. Method B. Synthesis of tert-butyl(2-(2-(2-((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)amino)ethoxy)ethoxy)ethyl)carbamate(I-35)

Step 1: tert-butyl (2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate

To a mixture of tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate(2 g, 8.03 mmol) and dess-martin periodinane in dichloromethane (20 mL)was added AcOH (1 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressureand purified by flash chromatography to give tert-butyl(2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (300 mg, 15.2%) as a colorlessoil. LC/MS (ESI, m/z): [M+1]⁺=248.1.

Step 2: tert-butyl(2-(2-(2-((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)amino)ethoxy)ethoxy)ethyl)carbamate(I-35)

To a mixture of I-5 (200 mg, 0.68 mmol) and(2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (176 mg, 0.714 mmol) in THE (5mL) was added AcOH (5 drops). The mixture was stirred at roomtemperature for 2 h. Then NaCNBH₃ (21.3 mg, 0.34 mmol) was added inportions. The reaction mixture was warmed to 40° C. and stirred for 2 h.The reaction mixture was poured into water and extract with EtOAc (3×20mL). The combined organic layers were concentrated under reducedpressure. The residue was purified via reverse phase columnchromatography (CH₃CN/H₂O=5%-80%) to give I-35 (70 mg, 19.6%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (br. s., 1H), 8.42 (dd,J=7.6, 1.5 Hz, 1H), 8.33 (dd, J=4.8, 1.5 Hz, 1H), 7.36-7.32 (m, 2H),7.17-7.13 (m, 1H), 6.92 (dd, J=8.8, 2.2 Hz, 1H), 6.79-6.76 (m, 1H), 5.91(br. s., 1H), 5.30 (br. s., 1H), 3.66-3.62 (m, 2H), 3.60-3.50 (m, 4H),3.41-3.29 (m, 4H), 3.12-2.95 (m, 4H), 2.71-2.65 (m, 1H), 2.12-2.01 (m,1H), 1.37 (s, 9H); LC/MS (ESI, m z): [M+1]⁺=526.55

Characterization data for further compounds prepared by Method B arepresented in Table 5 below. Compounds in Table 5 were prepared bymethods substantially similar to those described to prepare I-35.

TABLE 5 Compounds prepared according to Method B. LC/MS I-#Intermediates (ESI, m/z) ¹H NMR (400 MHz) I-50 I-5 + D [M + 1]⁺ =(DMSO-d₆) δ 11.09 (br. s., 1 H), 8.40 (dd, J = 1.6, 1.4 Hz, 1 517.3 H),8.32 (dd, J = 4.8, 1.3 Hz, 1 H), 7.43-7.21(m, 7 H), 7.16- 7.13 (m, 1 H),6.92-6.89(m, 1 H), 5.91 (br. s., 1 H), 5.39- 5.15 (m, 1 H), 4.48 (s, 2H), 3.66-3.63 (m, 2 H), 3.59- 3.56 (m, 8 H), 3.31-3.26 (m, 2 H),3.07-2.93 (m, 2 H), 2.72-2.64 (m, 1 H), 2.10-2.02 (m, 1 H)

Example 12. Synthesis of tert-butyl(2-(2-(2-(((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)methyl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate(I-36)

Step 1:3-(6-(aminomethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

A solution of I-32 (1.2 g, 3.95 mmol) in AcOH (10 mL) was addedPalladium 10% on Carbon (0.24 g) and platinum(IV) oxide (0.12 g). Thereactor system was sealed and purged three times with nitrogen followedby hydrogen. The system was pressurized with hydrogen (80 psi) andheated at 60° C. for 2 h. The mixture was cooled to r.t and filtered.The filtrate was diluted with water and freeze-dried to give3-(6-(aminomethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (0.4g, 33.1% yield) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=309.3

Step 2: tert-butyl(2-(2-(2-(((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)methyl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate(I-36)

To a solution of3-(6-(aminomethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (30mg, 0.097 mmol) in DMF (2 mL) was added HATU (55.5 mg, 0.15 mmol),2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oic acid (38.4 mg,0.15 mmol) and DIPEA (37.8 mg, 0.29 mmol) at r.t. under nitrogen. Thereaction was stirred at r.t for 2 h. The reaction mixture was directlypurified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) togive I-36 (3.0 mg, 5.6%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.52-8.32 (m, 3H), 8.06 (s, 1H), 7.47-7.44 (m, 1H), 7.35 (br s, 1H),7.25-7.22 (m, 2H), 5.97-5.93 (m, 1H), 4.81 (br s, 1H), 4.71-4.59 (m,2H), 4.07 (s, 2H), 3.72-3.49 (m, 4H), 3.37-3.35 (m, 2H), 3.20-2.88 (m,5H), 2.35-2.30 (m, 1H), 1.42 (s, 9H); LC/MS (ESI, m/z):[M−Boc+1]⁺=454.3.

Example 13. Synthesis of tert-butyl(2-(2-(3-((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)methyl)ureido)ethoxy)ethyl)carbamate(I-37)

To a solution of3-(6-(aminomethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (45mg, 0.15 mmol) in DMF (2 mL) was added 4-nitrophenyl(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)carbamate (54.0 mg, 0.15mmol) and triethylamine (22 mg, 0.22 mmol) at r.t. under nitrogen. Thereaction was stirred at r.t for 2 h. The reaction mixture was directlypurified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) togive I-37 (21 mg, 26.7%) as a colorless soil. ¹H NMR (400 MHz, DMSO-d₆)δ 11.14 (s, 1H), 8.53 (dd, J=7.8, 1.5 Hz, 1H), 8.41 (dd, J=4.8, 1.5 Hz,1H), 8.08 (s, 1H), 7.55 (br s, 1H), 7.43-7.41 (m, 1H), 7.28-7.24 (m,1H), 6.78-6.75 (m, 2H), 6.49-6.45 (m, 1H), 6.02-5.96 (m, 1H), 4.36 (d,J=5.8 Hz, 2H), 4.13-4.00 (m, 4H), 3.62-3.58 (m, 2H), 3.21-3.00 (m, 4H),2.76-2.64 (m, 2H), 1.36 (s, 9H); LC/MS (ESI, m/z): [M-Boc+1]=439.0.

Example 14. Synthesis of 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)methyl)carbamate(I-38)

I-38 was synthesized via the same method as I-37.

¹H NMR (400 MHz, DMS O-d₆) δ 11.14 (s, 1H), 8.54 (dd, J=7.7, 1.5 Hz,1H), 8.42 (dd, J=4.8, 1.5 Hz, 1H), 8.09 (s, 1H), 7.84-7.81 (m, 1H),7.58-7.55 (m, 1H), 7.44-7.41 (m, 1H), 7.28-7.24 (m, 1H), 6.77 (br s,1H), 6.01 (br s, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.13-3.97 (m, 5H),3.62-3.52 (m, 3H), 3.10-3.01 (m, 3H), 2.72-2.67 (m, 1H), 1.36 (s, 9H);LC/MS (ESI, m/z): [M−Boc+1]⁺=440.0.

Example 15. Synthesis of9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indole-2-carbonitrile (I-81)and 3-(2-(aminomethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-91)

Step 1:9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indole-2-carbonitrile (I-81)

A mixture of I-75 (120 mg, 0.4 mmol), dppf (44 mg, 0.08 mmol), Pd₂(dba)₃(36 mg, 0.04 mmol) and ZnCN₂ (94 mg, 0.8 mmol) in DMF was degassed withnitrogen, heated to 130° C. and stirred for 16 hours in sealed tube. Thereaction was cooled to r.t, diluted with water and extracted with EA.The combined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by via reverse phase column chromatography (CH₃CN/H₂O=5%-80%)to give I-81 (40 mg, 33% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.23 (s, 1H), 8.83 (d, J=8.4 Hz, 1H), 8.38 (d, J=7.8 Hz,1H), 7.91 (d, J=7.8 Hz, 1H), 7.76-7.56 (m, 2H), 7.44-7.29 (m, 1H), 6.11(s, 1H), 3.13-2.99 (m, 2H), 2.80-2.68 (m, 1H), 2.22-2.16 (m, 1H). LC/MS(ESI, m/z): [M+1]⁺=304.9.

Step 2:3-(2-(aminomethyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-91)

A mixture of I-81 (30 mg, 0.1 mmol), PtO₂ (10 mg) and Palladium 10% onCarbon (30 mg) in AcOH (5 mL). The reactor system was sealed and purgedthree times with nitrogen followed by hydrogen. The system waspressurized with hydrogen (80 psi) and heated at r.t for 2 h. Themixture was filtered and concentrated in vacuo. The residue was purifiedby by via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) to giveI-91 (10 mg, 33% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.55 (d, J=7.6 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.61-7.58(m, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.39-7.19 (m, 2H), 6.11 (s, 1H), 4.09(s, 2H), 3.50-3.20 (m, 3H), 3.05-2.96 (m, 1H), 2.77-2.61 (m, 1H),2.14-2.02 (m, 1H). LC/MS (ESI, m/z): [M+1]⁺=308.6.

Example 16. Synthesis of9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indole-4-carbonitrile (I-76)

I-76 was synthesized via the same method as I-81. ¹H NMR (400 MHz,DMSO-d₆) δ 11.23 (s, 1H), 8.66 (d, J=5.0 Hz, 1H), 8.39 (d, J=7.9 Hz,1H), 7.88-7.61 (m, 3H), 7.50-7.45 (m, 1H), 6.16 (s, 1H), 3.18-2.93 (m,2H), 2.80-2.63 (m, 1H), 2.26-2.11 (m, 1H); LC/MS (ESI, m/z):[M+1]⁺=305.1.

Example 17. Synthesis of3-(2-methyl-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-86)

A mixture of I-75 (31 mg, 0.1 mmol), methylboronic acid (18 mg, 0.3mmol), Pd (PPh₃)₄(36 mg, 0.04 mmol) and K₂CO₃ (40 mg, 0.3 mmol) in1,4-dioxane was degassed with nitrogen, heated to 100° C. and stirredfor 16 hours in sealed tube. The reaction was cooled to r.t, dilutedwith water and extracted with EA. The combined organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by via reverse phasecolumn chromatography (CH₃CN/H₂O=5%-80%) to give I-86 (6 mg, 20% yield)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.38 (d,J=7.6 Hz, 1H), 8.11 (d, J=7.6 Hz, 1H), 7.53-7.36 (m, 2H), 7.22-7.20 (m,1H), 7.11-7.08 (m, 1H), 5.98 (s, 1H), 3.14-2.89 (m, 2H), 2.67-2.63 (m,1H), 2.54 (s, 3H), 2.08-2.04 (m, 1H); LC/MS (ESI, m/z): [M+1]⁺=294.6.

Example 18. Synthesis of3-(4-methyl-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-86)

I-77 was synthesized via the same method as I-86. ¹H NMR (400 MHz,DMSO-d₆) δ 11.14 (s, 1H), 8.29 (d, J=4.9 Hz, 1H), 8.19 (d, J=7.8 Hz,1H), 7.65-7.60 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H),7.10 (d, J=5.0 Hz, 1H), 6.05 (s, 1H), 3.15-2.96 (m, 2H), 2.84 (s, 3H),2.72-2.67 (m, 1H), 2.14-2.07 (m, 1H); LC/MS (ESI, m/z): [M+1]⁺=293.6Example 19. Synthesis of3-(6-bromo-2-fluoro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-92)

To a stirred solution of I-84 (10 mg, 0.036 mmol) in DMF (1 mL) wasadded NBS (6 mg, 0.036 mmol) at rt. The mixture was stirred at roomtemperature overnight. The mixture was purified by Prep-HPLC to giveproduct I-92 (3 mg, 24% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.22 (s, 1H), 8.80 (t, J=8.4 Hz, 1H), 8.52 (s, 1H), 7.65 (s,2H), 7.07 (d, J=8.0 Hz, 1H), 5.99 (d, J=6.4 Hz, 1H), 3.03-2.99 (m, 2H),2.73-2.67 (m, 1H), 2.19-2.15 (m, 1H). LC/MS (ESI, m/z):[M+1]⁺=376.0/378.0.

Example 20. Synthesis of3-(2-(methylamino)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-79) and3-(2-(dimethylamino)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-80)

To a mixture of I-78 (50 mg, 0.17 mmol) and paraformaldehyde (10.2 mg,0.34 mmol) in THF (5 mL) was added AcOH (2 drops). The mixture wasstirred at room temperature for 2 h. Then NaCNBH₃ (21.4 mg, 0.34 mmol)was added. The reaction mixture was heated to 40° C. and stirredovernight. The reaction mixture was poured into water and extract withEtOAc. The combined organic layers was concentrated in vacuo. Theresidue was purified by Prep-HPLC to give I-79 (3.2 mg, 6.1%) and I-80(7.1 mg, 13% yield) as white solids. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (br.s., 1H), 8.02 (d, J=8.4 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.27-7.34 (m,1H), 7.24-7.16 (m, 2H), 6.30 (d, J=8.4 Hz, 1H), 5.66-5.61 (m, 1H), 4.59(br. s., 1H), 3.09-2.83 (m, 6H), 2.30-2.21 (m, 1H); LC/MS (ESI, m/z):[M+1]⁺=309.1; and ¹H NMR (400 MHz, CDCl₃) δ 8.14 (br. s., 1H), 8.05 (d,J=8.6 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.27-7.34 (m, 1H), 7.15-7.24 (m,2H), 6.43 (d, J=8.6 Hz, 1H), 5.57-5.52 (m, 1H), 3.17-2.92 (m, 8H),2.91-2.77 (m, 1H), 2.31-2.21 (m, 1H); LC/MS (ESI, m/z): [M+1]⁺=323.0.

Example 21. Synthesis ofN-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-2-yl)acetamide(I-90)

To a stirred solution of I-78 (30 mg, 0.102 mmol) in DCM (3 mL) wasadded acetyl chloride (3 drops) and pyridine (6 drops). The reactionmixture was stirred at r.t overnight. The reaction mixture wasconcentrated in vacuo and purified via reverse phase columnchromatography (CH₃CN/H₂O=5%-80%) to give I-90 (12 mg, 35.0%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H), 10.39 (s, 1H), 8.48(d, J=8.4 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.01 (br. s., 1H), 7.60-7.58(m, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 5.91-5.86 (m,1H), 3.06-2.90 (m, 1H), 2.80-2.63 (m, 1H), 2.14-2.20 (m, 5H); LC/MS(ESI, m/z): [M+1]⁺=337.1.

Example 22. Synthesis of3-(2-hydroxy-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-83)

I-82 (36 mg, 0.1 mmol) was added to boron tribromide 17% in methylenechloride (10 mL). The reaction mixture was heated to 50° C. and stirredfor 16 h under nitrogen atmosphere. The reaction was cooled to r.t andconcentrated under reduced pressure. The residue was purified viareverse phase column chromatography (CH₃CN/H₂O=5%-80%) to give I-83 (5.1mg, 15% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s,1H), 10.81 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.51(d, J=8.3 Hz, 1H), 7.39-7.29 (m, 1H), 7.21 (t, J=7.4 Hz, 1H), 6.52 (d,J=8.3 Hz, 1H), 5.85 (dd, J=12.8, 5.2 Hz, 1H), 3.16 (s, 1H), 3.04-2.91(m, 1H), 2.77-2.64 (m, 1H), 2.14-2.04 (m, 1H). LC/MS (ESI, m/z):[M+1]⁺=295.3.

Example 23. Synthesis of3-(3-(3-(2-(2-aminoethoxy)ethoxy)propyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-59)

Step 1: 3-bromo-5-(2-nitrophenyl)pyridine

A mixture of 1-bromo-2-nitrobenzene (4.0 g, 19.8 mmol),(5-bromopyridin-3-yl)boronic acid (4.8 g, 23.8 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (1.6 g, 1.98 mmol) and potassium carbonate (5.5g, 39.6 mmol) in acetonitrile (60 mL) and water (15 mL) was degassedwith nitrogen, heated to 80° C. and stirred for 2 hours under nitrogenatmosphere. The reaction was cooled to r.t and filtered. The filtratewas concentrated in vacuo. The residue was diluted with water, extractedwith EA. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography (Petroleumether/EtOAc=2:1) to give 3-bromo-5-(2-nitrophenyl)pyridine (3.2 g, 58.2%yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=280.1.

Step 2: tert-butyl(2-(2-((3-(5-(2-nitrophenyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate

A mixture of 3-bromo-5-(2-nitrophenyl)pyridine (1.4 g, 5.0 mmol),tert-butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (2.4 g, 10.0mmol), CuI (77 mg, 0.4 mmol), caesium carbonate (4.9 g, 15.1 mmol) andpalladium(II)bis(triphenylphosphine) dichloride (0.35 g, 0.5 mmol) inDMF (20 mL) was degassed with nitrogen, heated to 80° C. and stirred for1 hour under microwave condition. The reaction was cooled to r.t andfiltered. The filtrate was diluted with water, extracted with EA. Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography (Petroleum ether/EtOAc=4:1) to givetert-butyl(2-(2-((3-(5-(2-nitrophenyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(1.4 g, 63.3% yield) as a yellow oil. LC/MS (ESI, m/z): [M+1]⁺=442.1.

Step 3: tert-butyl(2-(2-((3-(9H-pyrido[2,3-b]indol-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate

A solution of tert-butyl(2-(2-((3-(5-(2-nitrophenyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(1.4 g, 3.17 mmol) in DMF (30 mL) was added Pd(OAc)₂ (3.6 mg, 0.016mmol) and 1,10-phenanthroline (20.0 mg, 0.11 mmol). The reactor systemwas sealed and purged three times with nitrogen followed by carbonmonoxide. The system was pressurized with carbon monoxide (100 psi) andheated at 140° C. for 17 h. The mixture was cooled to rt, diluted withwater and extracted with EA. The combined organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography (Petroleumether/EtOAc=2:1) to give tert-butyl(2-(2-((3-(9H-pyrido[2,3-b]indol-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(0.85 g, 65.4% yield) as a yellow oil. LC/MS (ESI, m/z): [M+1]⁺=410.1.

Step 4: tert-butyl(2-(2-((3-(9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate

To a stirred solution of tert-butyl(2-(2-((3-(9H-pyrido[2,3-b]indol-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(0.2 g, 0.49 mmol) and 18-crown-6 (26 mg, 0.098 mmol) in THE (4 mL) wasadded NaHMDS (0.37 mL, 2 M in THF, 0.73 mmol) dropwise at −30° C. undernitrogen atmosphere. The mixture was stirred for 1 h at −30° C. undernitrogen atmosphere. Then a solution of1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate(0.28 g, 0.73 mmol) in THF (2 mL) was added to the reaction dropwiseat−30° C. under nitrogen atmosphere. After addition, the mixture wasstirred for 2 h at −30° C. The reaction mixture was quenched by sat.aq.ammonium chloride and extracted with EA. The combined organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatography(Petroleum ether/EtOAc=2:1) to give tert-butyl(2-(2-((3-(9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(0.15 g, 48.4% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=641.8.

Step 5: tert-butyl(2-(2-(3-(9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-3-yl)propoxy)ethoxy)ethyl)carbamate

A solution of tert-butyl(2-(2-((3-(9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-3-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(150 mg, 0.23 mmol) in EA (10 mL) was added Palladium 10% on Carbon (30mg) and acetic acid (2 drops). The reactor system was sealed and purgedthree times with nitrogen followed by hydrogen. The system waspressurized with hydrogen and stirred for 17 h. The mixture was filteredand concentrated in vacuo to give tert-butyl(2-(2-(3-(9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-3-yl)propoxy)ethoxy)ethyl)carbamate(150 mg, quant.) as a yellow oil. LC/MS (ESI, m/z): [M+1]⁺=645.8

Step 6:3-(3-(3-(2-(2-aminoethoxy)ethoxy)propyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-59)

To a stirred solution of tert-butyl(2-(2-(3-(9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-3-yl)propoxy)ethoxy)ethyl)carbamate(0.14 g, 0.22 mmol) in toluene (2 mL) was added methanesulfonic acid (1mL). The reaction mixture was heated to 110° C. and stirred for 2 hunder nitrogen atmosphere. The reaction was cooled to r.t andconcentrated under reduced pressure to remove toluene. The residue waspurified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) togive3-(3-(3-(2-(2-aminoethoxy)ethoxy)propyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(3 mg, 3.3% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.43-8.39 (m, 2H), 8.29 (d, J=1.9 Hz, 1H), 8.20 (d, J=7.7 Hz, 1H),7.60-7.58 (m, 1H), 7.49 (t, J=7.4 Hz, 1H), 7.27 (t, J=7.4 Hz, 1H), 6.01(s, 1H), 3.59-3.51 (m, 8H), 3.47-3.43 (m, 4H), 2.90-2.78 (m, 4H),2.75-2.65 (m, 1H), 2.16-2.06 (m, 1H), 1.96-1.85 (m, 2H). LC/MS (ESI,m/z): [M+1]⁺=425.2

Example 24. Synthesis of3-(3-(3-(2-(2-hydroxyethoxy)ethoxy)propyl)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-54)

I-54 was synthesized via the same method as I-59 substitutingIntermediate C with((2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)methyl)benzene in Step 2. ¹H NMR(400 MHz, CDCl₃) δ 8.34-8.24 (m, 2H), 8.11-8.05 (m, 2H), 7.55-7.44 (m,1H), 7.35-7.28 (m, 2H), 5.37-5.32 (m, 1H), 3.81-3.58 (m, 9H), 3.52-3.48(m, 2H), 3.05-2.90 (m, 5H), 2.27-2.18 (m, 1H), 2.04-1.99 (m, 2H); LC/MS(ESI, m/z): [M+1]⁺=426.0

Example 25. Synthesis of3-(9H-pyrrolo[2,3-b:5,4-c′]dipyridin-9-yl)piperidine-2,6-dione (I-69)

Step 1: N-(4-bromopyridin-3-yl)pyridin-2-amine

A mixture of 4-bromopyridin-3-amine (1 g, 5.78 mmol), 2-iodopyridine(1.4 g, 6.94 mmol), palladium acetate (0.13 g, 0.58 mmol), xantphos(0.34 g, 0.58 mmol) and sodium tert-butoxide (0.83 g, 8.67 mmol) intoluene (20 mL) was degassed with nitrogen, heated to 130° C. andstirred for 17 hours under nitrogen atmosphere. The reaction was cooledto r.t and filtered. The filtrate was concentrated in vacuum. Theresidue was purified by column chromatography (Petroleumether/EtOAc=2:1) to give N-(4-bromopyridin-3-yl)pyridin-2-amine (1.0 g,69.4% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=251.1.

Step 2: 9H-pyrrolo[2,3-b:5,4-c′]dipyridine

A mixture of N-(4-bromopyridin-3-yl)pyridin-2-amine (1.0 g, 4.0 mmol),palladium acetate (90 mg, 0.40 mmol), potassium carbonate (0.83 g, 6.0mmol) and tricyclohexylphosphine tetrafluroborate (0.29 g, 0.80 mmol) inDMA (10 mL) was degassed with nitrogen, heated to 170° C. and stirredfor 2 hours under microwave conditions. The reaction was cooled to r.tand filtered. The filtrate was purified via reverse phase columnchromatography (CH₃CN/H₂O=5%-80%) to give9H-pyrrolo[2,3-b:5,4-c′]dipyridine (0.35 g, 52.2% yield) as a yellowsolid. LC/MS (ESI, m/z): [M+1]⁺=170.1.

Step 3: 1-(4-methoxybenzyl)-3-(9H-pyrrolo[2,3-b:5,4-c′]dipyridin-9-yl)piperidine-2,6-dione

To a stirred solution of 9H-pyrrolo[2,3-b:5,4-c′]dipyridine (0.5 g, 2.96mmol) and 18-crown-6 (0.16 g, 0.59 mmol) in THE (10 mL) was added NaHMDS(2.2 mL, 2 M in THF, 4.44 mmol) dropwise at −30° C. under nitrogenatmosphere. The mixture was stirred for 1 h at −30° C. under nitrogenatmosphere. Then a solution of1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate(1.7 g, 4.44 mmol) in THE (10 mL) was added to the reaction dropwiseat−30° C. under nitrogen atmosphere. After addition, the mixture wasstirred for 2 h at −30° C. and quenched by sat.aq. ammonium chloride.The residue was purified via reverse phase column chromatography(CH₃CN/H₂O=5%-80%) to give1-(4-methoxybenzyl)-3-(9H-pyrrolo[2,3-b:5,4-c′]dipyridin-9-yl)piperidine-2,6-dione(140 mg, 11.9% yield) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=401.8.

Step 4: 3-(9H-pyrrolo[2,3-b:5,4-c′]dipyridin-9-yl)piperidine-2,6-dione(I-69)

To a stirred solution of1-(4-methoxybenzyl)-3-(9H-pyrrolo[2,3-b:5,4-c′]dipyridin-9-yl)piperidine-2,6-dione(0.14 g, 0.35 mmol) in toluene (2 mL) was added methanesulfonic acid (2mL). The reaction mixture was heated to 110° C. and stirred for 2 hunder nitrogen atmosphere. The reaction was cooled to r.t andconcentrated under reduced pressure to remove toluene. The residue waspurified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) togive 3-(9H-pyrrolo[2,3-b:5,4-c′]dipyridin-9-yl)piperidine-2,6-dione (2.4mg, 2.4% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.57 (s,1H), 9.95 (s, 1H), 9.32 (d, J=7.0 Hz, 1H), 9.10 (d, J=6.8 Hz, 1H), 8.96(d, J=6.9 Hz, 1H), 8.04-7.87 (m, 1H), 7.40-7.37 (m, 1H), 6.19-6.14 (m,1H), 3.05-2.80 (m, 3H), 2.07-1.91 (m, 1H). LC/MS (ESI, m/z):[M+1]⁺=280.9.

Example 26. Synthesis of3-(3-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-39)

3-(3-Nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione wassynthesized via the same method as I-69.

3-(3-Amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-39)

A solution of 3-(3-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(40 mg, 0.12 mmol) in EA (10 mL) was added palladium 10% on Carbon (12mg) and acetic acid (1 drops). The reactor system was sealed and purgedthree times with nitrogen followed by hydrogen. The system waspressurized with hydrogen and stirred for 17 h. The mixture was filteredand concentrated in vacuo. The residue was purified via reverse phasecolumn chromatography (CH₃CN/H₂O=5%-80%) to give3-(3-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (6 mg, 16.5%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),8.05-8.03 (m, 1H), 7.89 (d, J=2.5 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H),7.53-7.32 (m, 2H), 7.18-7.14 (m, 1H), 5.89-5.86 (m, 1H), 4.96 (s, 2H),3.12-2.89 (m, 2H), 2.75-2.60 (m, 1H), 2.13-1.98 (m, 1H); LC/MS (ESI,m/z): [M+1]⁺=295.4.

Example 27. Synthesis of tert-butyl9-(2,6-dioxopiperidin-3-yl)-7,8-dihydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine-6(9H)-carboxylate(I-40)

To a mixture of I-55 (42 mg, 0.112 mmol) and Boc₂O (36.6 mg, 0.168 mmol)in THF (1 mL) and EA (3 mL) was added palladium on activated carbon 10%Pd (12 mg). The mixture was stirred at room temperature under hydrogenatmosphere overnight. The reaction mixture was filtered. The filtratewas concentrated under reduce pressure. The residue was purified byflash chromatography to give tert-butyl9-(2,6-dioxopiperidin-3-yl)-7,8-dihydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine-6(9H)-carboxylate(25 mg, 58.4%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 8.14 (d, J=3.9 Hz, 1H), 7.90 (d, J=7.0 Hz, 1H), 7.07 (dd, J=7.8,4.8 Hz, 1H), 5.54 (br. s., 1H), 4.41-4.58 (m, 2H), 3.76-3.71 (m, 2H),2.99-2.84 (m, 2H), 2.81-2.73 (m, 2H), 2.70-2.58 (m, 1H), 2.15-2.06 (m,1H), 1.44 (s, 9H); LC/MS (ESI, m/z): [M+1]⁺=385.2.

Example 28. Synthesis of3-(9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)piperidine-2,6-dione (I-56)

Step 1:3-(7,8-dihydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridin-9(6H)-yl)piperidine-2,6-dione

To a solution of3-(6-benzyl-7,8-dihydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridin-9(6H)-yl)piperidine-2,6-dione(250 mg, 0.668 mmol) in AcOH (5 mL) was added palladium on activatedcarbon 10% Pd (71 mg). The mixture was stirred at room temperatureovernight under hydrogen atmosphere. The reaction mixture was filtered.The filtrate was concentrated under reduce pressure. The residue waspurified by prep HPLC to give3-(7,8-dihydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridin-9(6H)-yl)piperidine-2,6-dione(120 mg, 63.3%) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=285.2.

Step 2: 3-(9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)piperidine-2,6-dione(I-56)

To a solution of3-(7,8-dihydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridin-9(6H)-yl)piperidine-2,6-dione(100 mg, 0.352 mmol) in CH₃CN (5 mL) and H₂O (1 mL) was added CAN (964mg, 1.76 mmol). The mixture was stirred at room temperature for 3h. Thereaction mixture was poured into water, treated with sat. aq NaHCO₃ topH 7 and extract with EtOAc (3×20 mL). The combined organic layers wereconcentrated under reduce pressure. The residue was purified by prepHPLC to give3-(9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)piperidine-2,6-dione (5.5 mg,5.6%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H), 9.88(s, 1H), 9.00-8.84 (m, 2H), 8.75 (d, J=3.9 Hz, 1H), 8.30 (d, J=6.6 Hz,1H), 7.67-7.63 (m, 1H), 6.31 (br. s., 1H), 3.09-2.94 (m, 2H), 2.81-2.76(m, 1H), 2.34-2.23 (m, 1H); LC/MS (ESI, m/z): [M+1]⁺=281.1.

Example 29. Synthesis of3-(6-(9-hydroxynonanoyl)-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)piperidine-2,6-dione(I-68)

3-(6-Benzyl-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dionewas synthesized en route to I-55.

Step 1: tert-butyl9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-5,7,8,9-tetrahydro-6H-pyrrolo[2,3-b:4,5-c′]dipyridine-6-carboxylate

To a mixture of3-(6-benzyl-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(42 mg, 0.112 mmol) and Boc₂O (398 mg, 1.824 mmol) in EA (5 mL) wasadded palladium on activated carbon 10% Pd (161 mg, 0.152 mmol). Themixture was stirred at room temperature under hydrogen atmosphereovernight. The reaction mixture was filtered and the filtrate wasconcentrated under reduce pressure. The residue was purified by flashchromatography eluting with EA/PE=54% to give tert-butyl9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-5,7,8,9-tetrahydro-6H-pyrrolo[2,3-b:4,5-c′]dipyridine-6-carboxylate(212 mg, 27.7%) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=505.2.

Step 2:1-(4-methoxybenzyl)-3-(5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)piperidine-2,6-dione

To a solution of tert-butyl9-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-5,7,8,9-tetrahydro-6H-pyrrolo[2,3-b:4,5-c′]dipyridine-6-carboxylate(212 mg, 0.421 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture wasstirred at room temperature for 2 h. The mixture was concentrated underreduce pressure and the residue was used directly in the next stepwithout further purification (160 mg, 94.2%) as a salt with TFA. LC/MS(ESI, m/z): [M+1]⁺=405.0.

Step 3:3-(6-(9-hydroxynonanoyl)-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a mixture of1-(4-methoxybenzyl)-3-(5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)piperidine-2,6-dione(212 mg, 0.421 mmol) and 9-hydroxynonanoic acid (237 mg, 1.364 mmol),HATU (518 mg, 1.364 mmol) in DCM (5 mL) was added DIPEA (480 mg, 3.72mmol). The mixture was stirred at room temperature for 2 h. The mixturewas diluted with DCM (20 mL) and washed with water. The organic layerwas concentrated under reduce pressure and the residue was purified viareverse phase column chromatography (CH₃CN/H₂O=5%-80%) to give3-(6-(9-hydroxynonanoyl)-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(355 mg, 51.1%) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=561.2.

Step 4:3-(6-(9-hydroxynonanoyl)-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)piperidine-2,6-dione(I-68)

To a solution of3-(6-(9-hydroxynonanoyl)-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(250 mg, 0.446 mmol) in toluene (5 mL) was added MsOH (430 mg, 4.46mmol). The mixture was warmed to 105° C. and stirred for 2 h. Thereaction mixture was cooled to room temperature and concentrated invacuum. The residue was purified via reverse phase column chromatography(CH₃CN/H₂O=5%-80%) to give3-(6-(9-hydroxynonanoyl)-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:4,5-c′]dipyridin-9-yl)piperidine-2,6-dione(5.7 mg, 2.9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (br.s., 1H), 8.17-8.11 (m, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.12-7.01 (m, 1H),5.51 (br. s., 1H), 4.76-4.59 (m, 2H), 4.33 (br. s., 1H), 3.98-3.76 (m,2H), 2.98-2.62 (m, 6H), 2.46-2.43 (m, 2H), 2.16-2.04 (m, 1H), 1.54-1.52(m, 2H), 1.42-1.37 (m, 2H), 1.32-1.17 (m, 9H); LC/MS (ESI, m/z):[M+1]⁺=441.2.

Example 30. Synthesis of tert-butyl4-(2-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)ethyl)piperazine-1-carboxylate(I-64)

Step 1:2-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)acetaldehyde

To a three neck flask was added Pd(tBu₃P)₂ (357.7 mg, 0.7 mmol) and ZnF₂(721 mg, 7 mmol). The mixture was degrassed with nitrogen, DMF (5 mL)was added. The mixture was stirred at room temperature for 10 min. Thenthe 3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (500 mg,1.4 mmol) in DMF was added followed by trimethyl(vinyloxy)silane (1.624g, 14 mmol). The reaction mixture was heated to 80° C. and stirred for1h. Then the reaction mixture was cooled to r.t, quenched by brine andextract with EtOAc (3×50 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium m sulfate, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(eluting with PE/EA=1:2) to give2-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)acetaldehyde(240 mg, 53.4%) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=322.0.

Step 2: tert-butyl4-(2-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)ethyl)piperazine-1-carboxylate(I-64)

To a mixture of2-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)acetaldehyde(100 mg, 0.312 mmol) and tert-butyl piperazine-1-carboxylate (75.3 mg,0.405 mmol) in DCE (5 mL) was added AcOH (3 drops). The mixture wasstirred at room temperature for 2 h. Then NaBH(OAc)₃ (132 mg, 0.624mmol) was added in portions. The reaction mixture was heated to 40° C.and stirred overnight. The reaction mixture was poured into water andextract with DCM (3×20 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by Prep-HPLC to give tert-butyl4-(2-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)ethyl)piperazine-1-carboxylate(33 mg, 21.5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s,1H), 8.52 (dd, J=7.7, 1.6 Hz, 1H), 8.40 (dd, J=4.8, 1.5 Hz, 1H), 8.08(s, 1H), 7.52-7.50 (m, 1H), 7.39-7.37 (m, 1H), 7.26-7.23 (m, 1H), 6.02(br. s., 1H), 3.37-3.31 (m, 4H), 3.08-2.95 (m, 2H), 2.94-2.86 (m, 2H),2.72-2.59 (m, 4H), 2.44-2.41 (m, 3H), 2.12-2.09 (m, 1H), 1.40 (s, 9H);LC/MS (ESI, m/z): [M+1]⁺=492.2.

Example 31. Synthesis of tert-butyl(1-(2-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)ethyl)piperidin-4-yl)carbamate(I-71)

I-71 was synthesized via the same method as I-64 substituting tert-butylpiperazine-1-carboxylate with tert-butyl piperidin-4-ylcarbamate. ¹H NMR(400 MHz, DMSO-d₆) δ 11.14 (s, 1H), 8.52 (d, J=7.6 Hz, 1H),8.40 (d,J=4.5 Hz, 1H), 8.06 (s, 1H) 7.52-7.50 (m, 1H), 7.38-7.23 (m, 2H), 6.76(d, J=7.4 Hz, 1H), 6.01 (br. s., 1H), 2.80-3.31 (m, 8H), 2.72-2.57 (m,4H), 2.12-2.00 (m, 3H), 1.72-1.69 (m, 2H), 1.38 (s, 9H); LC/MS (ESI,m/z): [M+1]⁺=506.2.

Example 32. Synthesis of3-(3-bromo-8H-thieno[2,3-b]indol-8-yl)piperidine-2,6-dione (I-89)

To a solution of 3-(8H-thieno[2,3-b]indol-8-yl)piperidine-2,6-dione (10mg, 0.035 mmol) in DMF (1 mL) was added NBS (6 mg, 0.035 mmol) under N₂and stirred for overnight at rt under N₂. The mixture was purified byprep-HPLC to give the product3-(3-bromo-8H-thieno[2,3-b]indol-8-yl)piperidine-2,6-dione (3 mg, 16%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H), 7.82(d, J=7.6 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.30-7.26 (m,1H), 7.21-7.17 (m, 1H), 5.91 (dd, J=5.2 Hz, J=13.6 Hz, 1H), 3.01-2.92(m, 1H), 2.76-2.61 (m, 2H), 2.25-2.21 (m, 1H). LC/MS (ESI, m/z):[M+1]⁺=363.0, 365.0.

Example 33. Synthesis of3-(3-chloro-8H-thieno[2,3-b]indol-8-yl)piperidine-2,6-dione (I-93)

To a solution of 3-(8H-thieno[2,3-b]indol-8-yl)piperidine-2,6-dione (15mg, 0.053 mmol) in DMF (1 mL) was added NCS (7 mg, 0.053 mmol) under N₂at room temperature overnight. The mixture was purified by prep-HPLC togive the product3-(3-chloro-8H-thieno[2,3-b]indol-8-yl)piperidine-2,6-dione (5 mg, 30%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H), 7.81(d, J=7.6 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.30-7.26 (m,1H), 7.21-7.17 (m, 1H), 5.91 (dd, J=5.2 Hz, J=13.6 Hz, 1H), 3.02-2.93(m, 1H), 2.75-2.58 (m, 2H), 2.25-2.20 (m, 1H). LC/MS (ESI, m/z):[M+1]⁺=319.0.

Example 34. Synthesis of3-3-(7-Bromopyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-102)

Step 1:3-(7-Bromopyrido[2,3-b]indol-9-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

To a mixture of 7-bromo-9H-pyrido[2,3-b]indole (300 mg, 1.21 mmol) and4A MS (100 mg) in THF (5 mL) was added t-BuOK (272 mg, 2.43 mmol) at 0°C. After stirring for 1 hr, a solution of[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (694 mg, 1.82 mmol) in THF (2 mL) was addedinto the above mixture dropwise at 0° C. The reaction mixture wasstirred at 25° C. for 10 hrs. On completion, the mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified byreverse phase (0.1% FA) to give the title compound (100 mg, 17% yield)as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.60 (dd, J=1.6, 7.6 Hz,1H), 8.45 (d, J=3.2 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.46 (dd, J=1.6,8.2 Hz, 1H), 7.31 (dd, J=4.8, 7.6 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H),7.18-7.13 (m, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.22-6.11 (m, 1H), 4.88-4.79(m, 2H), 3.73 (s, 3H), 3.19-3.11 (m, 2H), 2.94-2.88 (m, 1H), 2.23-2.16(m, 1H).

Step 2: 3-3-(7-Bromopyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-103)

To a solution of3-(7-bromopyrido[2,3-b]indol-9-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione(60.0 mg, 125 umol) in toluene (2 mL) was added AlCl₃ (83.6 mg, 627umol). The reaction mixture was stirred at 80° C. for 2 hrs. Oncompletion, the mixture was quenched with water (20 mL), extracted withEA (2×20 mL). The organic layer was concentrated in vacuo. The residuewas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 39%-66%, 9 min) to give thetitle compound (11.0 mg, 25% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.16 (s, 1H), 8.60 (dd, J=1.6, 7.6 Hz, 1H), 8.46 (dd, J=1.2,4.8 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 7.46 (dd, J=1.6, 8.4Hz, 1H), 7.31 (dd, J=4.8, 7.6 Hz, 1H), 6.10-5.95 (m, 1H), 3.22-3.08 (m,1H), 3.05-2.92 (m, 1H), 2.78-2.65 (m, 1H), 2.20-2.10 (m, 1H); LC-MS(ESI⁺) m z 358.0, 360.0 (M+H, M+3)⁺.

Example 35. Synthesis of3-(4-bromo-8H-thieno[2,3-b]indol-8-yl)piperidine-2,6-dione (I-103)

Step 1—3-(2-bromo-6-nitro-phenyl)thiophene

A mixture of 3-thienylboronic acid (10 g, 78 mmol),1-bromo-2-iodo-3-nitro-benzene (26 g, 78 mmol), Pd(PPh₃)₄(4.5 g, 3.91mmol) and NaOH (9.4 g, 234 mmol) in THF (240 mL), H₂O (120 mL) wasdegassed and purged with N₂ for 3 times. And then the mixture wasstirred at 90° C. for 12 hrs under N₂ atmosphere. The solution wasdiluted with water (200 mL) and extracted with ethyl acetate (200 mL*2).The combined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=40/1 to 10/1) to give the title compound (20 g, 81%yield) as a yellow solid. 1H NMR (400 MHz, CDCl₃) δ=7.80 (dd, J=1.2, 8.4Hz, 1H), 7.64 (m, 1H), 7.35 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.17 (dd,J=1.2, 2.8 Hz, 1H), 7.02 (m, 1H).

Step 2—8-bromo-4H-thieno[2,3-b]indole

3-(2-bromo-6-nitro-phenyl)thiophene (2 g, 7.04 mmol) and PPh₃ (5.54 g,21 mmol) were taken up into a microwave tube in DCB (10 mL). The sealedtube was heated at 200° C. for 2 hrs under microwave. The reactionmixture was filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=50:1 to 10/1) to get the title compound (0.5 g, 28%yield) as a yellow solid. LC-MS (ESI⁺) m/z 252.0 (M+H)⁺

Step3—3-(8-bromothieno[2,3-b]indol-4-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

t-BuOK (445 mg, 3.97 mmol) was added to a solution of8-bromo-4H-thieno[2,3-b]indole (500 mg, 1.98 mmol) in THE (10 mL) at 0°C. The resulting mixture was stirred at 0° C. for 30 min. Then asolution of[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate(1.1 g, 2.97 mmol) in THE (10 mL) was added slowly at 0° C. Afteraddition, the resulting solution was stirred at 0-25° C. for 11.5 hrsunder N₂ atmosphere. The reaction mixture was quenched by water (10 mL)and extracted with ethyl acetate (3*20 mL). The combined organic phaseswere concentrated under reduced pressure to give a residue. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=10/1 to 3/1) to give the title compound (230 mg, 23% yield) as ayellow liquid. LC-MS (ESI⁺) m/z 485.0 (M+H)⁺.

Step 4—3-(8-bromothieno[2,3-b]indol-4-yl)piperidine-2,6-dione

To a solution of3-(8-bromothieno[2,3-b]indol-4-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione(100 mg, 0.21 mmol) in toluene (1.0 mL) was added AlCl₃ (138 mg, 1.03mmol). The mixture was stirred at 80° C. for 1 hr. The reaction mixturewas concentrated under reduced pressure to give a residue. The residuewas diluted with ethyl acetate (20 mL) and then quenched by addition HCl(2M, 20 mL) at 0° C. and extracted with ethyl acetate (15 mL*2). Thecombined organic layers were concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=10/1 to 1/1) to give the title compound (40 mg, 37%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=11.27 (s, 1H),7.67-7.62 (m, 2H), 7.39 (d, J=7.6 Hz, 1H), 7.27-7.20 (m, 2H), 5.95 (m,1H), 3.04-2.92 (m, 1H), 2.82-2.71 (m, 2H), 2.31-2.24 (m, 1H); LC-MS(ESI⁺) m/z 365.0 (M+H)⁺.

Example 36. Synthesis of3-(6-bromo-2-chloro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-104)

Step 1: N-(2-iodophenyl)acetamide

To a solution of 2-iodoaniline (23.6 g, 108 mmol) in DCM (250 mL) wasadded TEA (13.1 g, 129 mmol) and cooled to 0° C. Then acetylchloride(9.30 g, 119 mmol) was added to the reaction mixture at 0° C. bydropwise and stirred at 20° C. for 2 hours. On completion, the reactionmixture was quenched by water (200 mL) and extracted withdichloromethane (3×100 mL). The extracts was washed by brine (100 mL)and dried over anhydrous sodium sulfate, filtered and concentrated invacuo to get the crude residue. The residue was purified by columnchromatography (SiO₂, petroleum ether:dichloromethane:ethylacetate=1:0:0 to 10:5:1) to give the title compound (25 g, 82% yield) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (d, J=7.6 Hz, 1H),7.78 (d, J=8.0 Hz, 1H), 7.48 (s, 1H) 7.35 (td, J1=1.2 Hz, J2=8.4 Hz,1H), 6.85 (t, J=7.2 Hz, 1H), 2.25 (s, 3H); LC-MS (ESI, m/z):[M+1]⁺=261.7.

Step 2: N-(2-(2,6-dichloropyridin-3-yl)phenyl)acetamide

To a solution of N-(2-iodophenyl)acetamide (5 g, 19.2 mmol) and(2,6-dichloro-3-pyridyl)boronic acid (3.67 g, 19.2 mmol) in dioxane (100mL) and H₂O (20 mL). Then Na₂CO₃ (6.09 g, 57.5 mmol) and Pd(PPh₃)₄(1.11g, 958 umol) were added to the mixture under nitrogen protection. Thenthe reaction mixture was stirred at 100° C. for 12 hours. On completion,the reaction mixture was quenched by water (100 mL) and extracted withethyl acetate (3×50 mL). The extracts was washed by brine (50 mL) anddried over anhydrous sodium sulfate, filtered and concentrated in vacuoto get the crude residue. The residue was purified by columnchromatography (SiO2, petroleum ether:dichloromethane:petroleumether=0:0:1 to 1:1:2) to give the title compound (2.3 g, 34% yield) as ayellow solid. LC-MS (ESI, m/z): [M+1]⁺=281.3.

Step 3: 2-chloro-9H-pyrido[2,3-b]indole

To a mixture of N-[2-(2,6-dichloro-3-pyridyl)phenyl]acetamide (1.7 g,6.05 mmol) and K₂CO₃ (5.01 g, 36.3 mmol) in DMF (30 mL) was added NaH(483.70 mg, 12.09 mmol, 60% purity) under nitrogen protection. Then themixture was stirred at 100° C. for 3 hours. On completion, the reactionmixture was poured into ice water (200 mL) and stirred for half an hour.Then the suspension was filtered to get the solid and dried in vacuo togive the title compound (1.2 g, 93% yield) as a yellow solid. LC-MS(ESI, m/z): [M+1]⁺=203.4.

Step 4: 6-bromo-2-chloro-9H-pyrido[2,3-b]indole

To a suspension of 2-chloro-9H-pyrido[2,3-b]indole (1 g, 4.93 mmol) inDCM (20 mL) was added Br₂ (946 mg, 5.92 mmol) in DCM (10 mL) and stirredat 20° C. for 1 hour. On completion, the reaction mixture wasconcentrated in vacuo and the residue poured into ice water (100 mL).Then suspension was quenched by saturated sodium sulfite aqueoussolution (10 mL) and adjust PH=9 by saturated sodium bicarbonate aqueoussolution. The solids was collected by filtration and triturated by ethylacetate:petroleum ether=1:1(50 mL) to give the title compound (1.3 g,84% yield) as a yellow solid. LC-MS (ESI, m/z): [M+1]⁺=283.0.

Step 5:3-(6-bromo-2-chloro-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of 6-bromo-2-chloro-9H-pyrido[2,3-b]indole (1.1 g, 3.52mmol) and 18-crown-6 (186 mg, 703 umol) in THE (20 mL) was added NaHMDS(1 M, 5.27 mL) at −30° C. by dropwise. After stirred at this temperaturefor 1 hour, [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (2.01 g, 5.27 mmol) in THE (20 mL) was addedto the reaction mixture by dropwise and stirred at 0° C. for another 2hours. On completion, the reaction mixture was diluted with ethylacetate (100 mL) and quenched by saturated ammonia chloride aqueoussolution (50 mL). The organic layers was washed by water (30 mL) andbrine (30 mL) and dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to get the crude residue. The residue was purifiedby column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to5:1) to give the title compound (1.8 g, 99% yield) as a white solid.LC-MS (ESI, m/z): [M+1]⁺=514.1.

Step 6:3-(6-bromo-2-chloro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a mixture of3-(6-bromo-2-chloro-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1.70 g, 3.32 mmol) in toluene (40 mL) was addedAlCl₃ (1.77 g, 13.3 mmol) and stirred at 80° C. for 0.5 hour. Oncompletion, the reaction mixture was concentrated in vacuo and theresidue was diluted with ethyl acetate (50 mL). Then the solution wasquenched by 1N hydrochloric acid aqueous solution (20 mL) and water (20mL). The mixture was extracted with ethyl acetate (3×30 mL) and washedby brine (30 mL), the extracts was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to get the crude residue. The cruderesidue was purified by silica gel chromatography (petroleum ether:ethylacetate:dichloromethane=10:1:1 to 1:1:1) to give the title compound (0.8g, 90% purity, 61.46% yield) as a gray solid. The product (50 mg, 90%purity) was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 56%-76%, 9min) to give the title compound (27.1 mg, 49.1% yield, 99.2% purity) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.22 (s, 1H), 8.69 (d, J=8.0Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 7.70-7.63 (m, 2H), 7.41 (d, J=8.0 Hz,1H), 6.03 (s, 1H), 3.05-3.01 (m, 2H), 2.74-2.71 (m, 1H), 2.18 (m, 1H);LC-MS (ESI, m/z): [M+1]⁺=394.1.

Example 37. Synthesis of3-(9H-pyrrolo[2,3-b:5,4-b′]dipyridin-9-yl)piperidine-2,6-dione (I-3)

Step 1: 3-chloro-N-(pyridin-2-yl)pyridin-2-amine

A mixture of 2,3-dichloropyridine (5.0 g, 34.0 mmol), pyridin-2-amine(3.5 g, 37.4 mmol), Pd(OAc)₂ (0.38 g, 1.70 mmol), PPh₃ (0.89 g, 3.40mmol) and t-BuONa (3.9 g, 40.8 mmol) in toluene (80 mL) was sparged withargon for about 10 min, placed under an argon atmosphere, and heated to120° C. for 17 hours. The reaction mixture was cooled to roomtemperature and concentrated in vacuo. The residue was diluted withwater (50 mL), extracted with EA (80 mL×2). The combined organic layerwas washed with brine (50 mL×2), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelcolumn chromatography (PE:EA=4/1) to give the product (4.3 g, 61.7%) asa yellow solid. LC-MS (ESI⁺): m/z 206.2 (M+H)⁺.

Step 2: 9H-pyrrolo[2,3-b:5,4-b′]dipyridine

A mixture of 3-chloro-N-(pyridin-2-yl)pyridin-2-amine (0.5 g, 2.44mmol), Pd(OAc)₂ (55.7 mg, 0.24 mmol), Tricyclohexylphosphoniumtetrafluoroborate (0.18 g, 0.49 mmol) and DBU (0.74 g, 4.88 mmol) in DMA(10 mL) was added to the sealed tube. The mixture was sparged with argonfor about 10 min, placed under an argon atmosphere, and heated to 170°C. for 10 hours in microwave condition. The reaction mixture was cooledto room temperature and diluted with water (30 mL), extracted with EA(40 mL×2). The combined organic layer was washed with water (40 mL×2)and brine (40 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gel columnchromatography (PE:EA=2/1) to give the product (0.32 g, 78%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.71-8.59 (m, 2H), 8.39-8.30 (m, 2H),7.29-7.25 (m, 2H). LC-MS (ESI⁺): m/z 170.2 (M+H)⁺.

Step 3:1-(4-methoxybenzyl)-3-(9H-pyrrolo[2,3-b:5,4-b′]dipyridin-9-yl)piperidine-2,6-dione

To a stirred solution of 9H-pyrrolo[2,3-b:5,4-b′]dipyridine (320 mg,1.89 mmol)

in DMF (10 mL) was added t-BuOK (254 mg, 2.27 mmol) at 0° C. undernitrogen atmosphere. The mixture was stirred at 0-10° C. for 1 hour.Then 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yltrifluoromethanesulfonate (1.082 g, 2.84 mmol) in DMF (2 mL) was addedto the reaction mixture at 0-10° C. during 10 minutes. After addition,the mixture was stirred at room temperature for 2 hours. On completion,the reaction was quenched by water and extracted with EA. The combinedorganic layer was washed with water and brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography (CH2Cl2/MeOH=20:1 to 10:1) to give1-(4-methoxybenzyl)-3-(9H-pyrrolo[2,3-b:5,4-b′]dipyridin-9-yl)piperidine-2,6-dione(200 mg, 27% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=401.5.

Step 4: 3-(9H-pyrrolo[2,3-b:5,4-b′]dipyridin-9-yl)piperidine-2,6-dione(I-3)

To a stirred solution of1-(4-methoxybenzyl)-3-(9H-pyrrolo[2,3-b:5,4-b′]dipyridin-9-yl)piperidine-2,6-dione(200 mg, 0.5 mmol) in toluene (5 mL) was added methanesulfonic acid (1mL). The reaction mixture was heated to 110° C. and stirred for 2 hunder nitrogen atmosphere. The reaction was cooled to r.t andconcentrated under reduced pressure to remove toluene. The residue waspurified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) togive 3-(9H-pyrrolo[2,3-b:5,4-b′]dipyridin-9-yl)piperidine-2,6-dione (16mg, 11% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d,J=1.6 Hz, 1H), 8.49 (d, J=1.6 Hz, 1H), 8.34 (d, J=1.6 Hz, 1H), 8.33 (d,J=1.6 Hz, 1H), 8.12 (br s, 1H), 7.28-7.25 (m, 2H), 6.07 (dd, J=12.6, 5.4Hz, 1H), 3.47 (ddd, J=30.2, 13.2, 5.0 Hz, 1H), 3.04-2.87 (m, 2H),2.35-2.28 (m, 1H); LC/MS (ESI, m/z): [M+1]⁺=281.1.

Example 38. Synthesis of3-(7-chloro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (I-106)

Step 1: 3-(4-chlorophenyl)-2-nitropyridine

A mixture of 3-iodo-2-nitropyridine (2 g, 8 mmol),(4-chlorophenyl)boronic acid (1.5 g, 9.6 mmol), Na₂CO₃ (1.7 g, 16 mmol)and Pd(PPh₃)₄(277 mg, 0.24 mmol) in dioxane (20 mL) and water (10 mL)was degassed with nitrogen, heated to 110° C. and stirred for 18 hoursunder nitrogen atmosphere. The reaction was cooled to r.t, filtered andconcentrated in vacuo. The residue was diluted with water, extractedwith EA. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography (Petroleumether/EtOAc=3:1) to give 3-(4-chlorophenyl)-2-nitropyridine (1.4 g, 75%yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=234.6.

Step 2: 7-chloro-9H-pyrido[2,3-b]indole

A mixture of 3-(4-chlorophenyl)-2-nitropyridine (1 g, 4.27 mmol) andPPh₃ (3.36 g, 12.82 mmol) in DCB (5 mL) was heated at 200° C. for 2 hrsunder microwave condition. The reaction mixture was cooled to r.t,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (Petroleum ether/Ethyl acetate=1:1 togive 7-chloro-9H-pyrido[2,3-b]indole (112 mg, 13% yield) as a blacksolid. LC/MS (ESI, m/z): [M+1]⁺=202.9.

Step 3:3-(7-chloro-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a stirred solution of 7-chloro-9H-pyrido[2,3-b]indole (112 mg, 0.554mmol) and 18-crown-6 (44 mg, 0.166 mmol) in THF (10 mL) was added NaHMDS(0.42 mL, 2 M in THF) dropwise at −30° C. under nitrogen atmosphere. Themixture was stirred for 1 h at −30° C. under nitrogen atmosphere. Then asolution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yltrifluoromethanesulfonate (316.6 mg, 0.831 mmol) in THE (10 mL) wasadded to the reaction dropwise at−30° C. under nitrogen atmosphere.After addition, the mixture was stirred for 2 h at −30° C. and quenchedby sat.aq. ammonium chloride, extracted with EA. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography (Petroleum ether/EtOAc=1:1) to give3-(7-chloro-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(94 mg, 84.4% yield) as a pale yellow solid.

Step 4: 3-(7-chloro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(I-106)

To a stirred solution of3-(7-chloro-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(94 mg, 0.22 mmol) in toluene (5 mL) was added methanesulfonic acid (1mL). The reaction mixture was heated to 110° C. and stirred for 2 hunder nitrogen atmosphere. The reaction was cooled to r.t andconcentrated under reduced pressure to remove toluene. The residue waspurified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%) togive 3-(7-chloro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (11 mg,16% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (dd, J=1.3,4.9 Hz, 1H), 8.30 (dd, J=1.3, 7.7 Hz, 1H), 8.16 (br. s., 1H), 8.00 (d,J=8.1 Hz, 1H), 7.29 (dd, J=1.5, 8.4 Hz, 1H), 7.25-7.20 (m, 1H), 5.83(dd, J=4.8, 12.4 Hz, 1H), 3.18-2.88 (m, 3H), 2.37-2.22 (m, 1H). LC/MS(ESI, m/z): [M+1]⁺=314.0.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications, andnon-patent publications referred to in this specification areincorporated herein by reference in their entireties, including U.S.provisional application nos. 62/694,924, filed Jul. 6, 2018, 62/820,634,filed Mar. 19, 2019, and 62/863,949, filed Jun. 19, 2019.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1-11. (canceled)
 12. A method of treating a CRBN-mediated disorder,disease, or condition in a patient comprising administering to saidpatient a compound of formula I-d:

a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof, wherein: X¹ is —CH₂— or —C(O)—, X² is a carbonatom; X³ is —CH₂—; R¹ is hydrogen; each R² is independently hydrogen,deuterium, R³, halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR,—C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,—OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,—N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; each R³ isindependently an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; each R is independently hydrogen, or an optionally substitutedgroup selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated orpartially unsaturated heterocyclic having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen aretaken together with their intervening atoms to form a 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur; each L is independently a covalent bond ora bivalent, saturated or unsaturated, straight or branched C₁₋₅₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by —C(D)(H)—, —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—,—Si(OH)(R)—, —Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—,—OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—,—N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—,

wherein: each -Cy- is independently an optionally substituted bivalentring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-7membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-7 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and an 8-10 memberedbicyclic heteroarylenyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; Ring A is tricyclic ring

wherein each of Ring B and Ring C is independently a fused ring selectedfrom 6-membered aryl containing 0-2 nitrogens and a 5-memberedheteroaryl with 1-2 heteroatoms independently selected from nitrogen,oxygen or sulfur;

is a single or double bond: L¹ is a covalent bond; each of n isindependently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and m is 0, 1, or
 2. 13.The method of claim 12, wherein the disorder is selected fromproliferative disorders, neurological disorders and disorders associatedwith transplantation.
 14. The method of claim 13, wherein the disorderis a proliferative disorder.
 15. The method of claim 14, wherein theproliferative disorder is a hematological cancer.
 16. The method ofclaim 14, wherein the proliferative disorder is a leukemia.
 17. Themethod of claim 16, wherein the leukemia is selected from the groupconsisting of acute leukemia, acute lymphoblastic leukemia (ALL),chronic lymphocytic leukemia (CLL), acute myelogenous leukemia, acutemyeloid leukemia (AML), adult acute basophilic leukemia, adult acuteeosinophilic leukemia, adult acute megakaryoblastic leukemia, adultacute minimally differentiated myeloid leukemia, adult acute monoblasticleukemia, adult acute monocytic leukemia, adult acute myeloblasticleukemia with maturation, adult acute myeloblastic leukemia withoutmaturation, adult acute myeloid leukemia with abnormalities, adult acutemyelomonocytic leukemia, adult erythroleukemia, adult pure erythroidleukemia, secondary acute myeloid leukemia, untreated adult acutemyeloid leukemia, adult acute myeloid leukemia in remission, adult acutepromyelocytic leukemia with PML-RARA, alkylating agent-related acutemyeloid leukemia, prolymphocytic leukemia, and chronic myelomonocyticleukemia.
 18. The method of claim 14, wherein the proliferative disorderis a lymphoma.
 19. The method of claim 18, wherein the lymphoma isselected from the group consisting of adult grade III lymphomatoidgranulomatosis, adult nasal type extranodal NK/T-cell lymphoma,anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma,cutaneous B-Cell non-Hodgkin lymphoma, extranodal marginal zone lymphomaof mucosa-associated lymphoid tissue, hepatosplenic T-cell lymphoma,intraocular lymphoma, lymphomatous involvement of non-cutaneousextranodal site, mature T-cell and NK-cell non-Hodgkin lymphoma, nodalmarginal zone lymphoma, post-transplant lymphoproliferative disorder,recurrent adult Burkitt lymphoma, recurrent adult diffuse large celllymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adultdiffuse small cleaved cell lymphoma, recurrent adult grade IIIlymphomatoid granulomatosis, recurrent adult immunoblastic lymphoma,recurrent adult lymphoblastic lymphoma, recurrent adult T-cellleukemia/lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma,recurrent grade 1 follicular lymphoma, recurrent grade 2 follicularlymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle celllymphoma, recurrent marginal zone lymphoma, recurrent mycosis fungoidesand Sezary syndrome, recurrent small lymphocytic lymphoma, refractorychronic lymphocytic leukemia, refractory hairy cell leukemia, Richtersyndrome, small intestinal lymphoma, splenic marginal zone lymphoma,T-cell large granular lymphocyte leukemia, testicular lymphoma,Waldenstrom macroglobulinemia, adult T-cell leukemia-lymphoma,peripheral T-cell lymphoma, B-cell lymphoma, Hodgkin's disease,cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma,mantle cell lymphoma, non-Hodgkins lymphoma, central nervous systemlymphoma, refractory primary-cutaneous large B-cell lymphoma (Leg-type),relapsed or refractory chronic lymphocytic leukemia, refractory anemia,refractory anemia with excess blasts, refractory anemia with ringedsideroblasts, refractory cytopenia with multilineage dysplasia, andsecondary myelodysplastic syndromes.
 20. The method of claim 13, whereinthe disorder is a neurological disorder.
 21. The method of claim 20,wherein the neurological disorder is Alzheimer's disease.
 22. The methodof claim 13, wherein the disorder is a disorder associated withtransplantation.
 23. The method of claim 22, wherein the disorderassociated with transplantation is graft-versus-host disease.
 24. Themethod of claim 12, wherein X¹ is —C(O)—.
 25. The method of claim 12,wherein each R² is independently hydrogen, R³, halogen, —CN, —NO₂, —OR,—SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, or—C(O)N(R)₂.
 26. The method of claim 12, wherein each L is independentlya bivalent, saturated or unsaturated, straight or branched C₁₋₂₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by -Cy-, —O—, —N(R)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—,—S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—,or —N(R)C(O)O—.
 27. The method of claim 12, wherein each L isindependently a bivalent, saturated or unsaturated, straight or branchedC₁₋₁₀ hydrocarbon chain, wherein 0-6 methylene units of L areindependently replaced by -Cy-, —O—, —N(R)—, —S—, or —C(O)—.
 28. Themethod of claim 12, wherein each of Ring B and Ring C is independently afused ring selected from 6-membered aryl containing 0-2 nitrogens. 29.The method of claim 12, wherein each L is independently a covalent bond.30. The method of claim 12, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 31. The method of claim12, wherein the pharmaceutical composition comprises a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.